WO2022117090A1

WO2022117090A1 - Polycyclic compound, and preparation method therefor and use thereof

Info

Publication number: WO2022117090A1
Application number: PCT/CN2021/135493
Authority: WO
Inventors: 黄金昆; 谢德建; 王寿平; 冯超阳; 刘俊强; 张伟; 鲁岳
Original assignee: 成都科岭源医药技术有限公司
Priority date: 2020-12-03
Filing date: 2021-12-03
Publication date: 2022-06-09
Also published as: CN114591351B; CN114591351A

Abstract

A polycyclic compound represented by formula I or a stereoisomer, a solvate, a salt, an ester, a prodrug or a hydrate thereof, and a preparation method therefor and the use thereof. The compound has a good inhibitory effect on TYK2, and can be used for treating diseases related to TYK2 kinase dysfunction, such as cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, respiratory diseases and heart diseases. The compound has high selectivity for a TYK2 JH2 binding domain and is safe to use with few toxic side effects. The compound can be used in the preparation of a TYK2 inhibitor and a drug for treating diseases related to TYK2 kinase dysfunction, and thus possesses good application prospects.

Description

A kind of polycyclic compound and its preparation method and use

technical field

The invention relates to the field of medicinal chemistry, in particular to a polycyclic compound and a preparation method and application thereof.

Background technique

Cytokines play an important role in the regulation of immunity and inflammation. Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the process of signal transmission from extracellular to nucleus of various cytokines. The JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3 and TYK2, and each subtype mediates different types of cytokine signaling pathways. JAK1, JAK2 and TYK2 are expressed in various human tissue cells, and JAK3 is mainly expressed in various hematopoietic tissue cells.

JAK family members are composed of four JAK homology regions (JAK homology regions, JH), including a catalytically activated kinase domain (JH1), a catalytically inactive kinase-like domain (JH2), and a SH2-like domain. (JH3) and four FERM domains (JH4-7). Among them, the JH2 domain is the most special structure. It has a high degree of similarity with the amino acid sequence of the JH1 domain. However, due to the lack of several key amino acids, it does not have phosphatase activity, so it cannot exert catalytic activity. Therefore, Known as the kinase-like domain, and play a role in regulating catalytic activity.

When the cytokine binds to the transmembrane receptor, the JAK protein coupled to the intracellular receptor is phosphorylated, and the activated JAK further phosphorylates the receptor. The phosphorylated tyrosine site can be used as a structure containing SH2. The binding site of the protein with the SH2 domain, so the signal transducer and activator of transcription (STAT) with the SH2 domain can be recruited to the receptor and phosphorylated by JAKs, and the phosphorylated STAT is formed by dimerization After the dimer is transferred to the nucleus, it combines with the target gene and promotes its transcription, thereby regulating the growth, activation, differentiation and other functions of various cells.

TYK2 is the first subtype discovered in the JAK family, and a number of cytokine signaling pathways that require TYK2 to participate in the transduction have been found, including interleukin (IL) and interferon (IFN) with different subtypes. In these signaling pathways, TYK2 is coupled to transmembrane cytokine receptor proteins including IFNAR1, IL-12Rβ1, IL-10R2 and IL-13Rα1, and to another receptor chain coupled to JAK1 or JAK2 via heterologous Dimerization forms distinct cytokine receptor complexes that provide the binding sites required for STAT binding. Different cytokines, including IFN-α, IL-6, IL-12, and IL-23, activate downstream specific STAT proteins by utilizing different cytokine receptor complexes. Some cytokines make helper T cells Th17, Th1, B cells or myeloid cells through TYK2-mediated signaling pathways, including systemic lupus erythematosus, psoriasis, lupus nephritis, Sjogren's disease, Crohn's disease, systemic sclerosis, etc. Function in autoimmune and chronic inflammatory diseases. Several studies have shown that TYK2 deletion mutations can effectively inhibit the occurrence of immune diseases such as allergy, autoimmunity and inflammation. For example, IL-23 plays a crucial role in the occurrence and development of psoriasis. The latest research shows that the pathogenesis of psoriasis is that endogenous unknown antigens activate antigen-presenting cells (APCs) to secrete IL-23. IL-23 activates Th17 cells to secrete IL-17 and other cytokines, and induces keratinocytes to differentiate and secrete IL-23. , which further stimulates validation and keratinocyte proliferation to produce psoriasis. TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23, and inhibition of JAK2 can lead to anemia and other blood-related side effects, so targeting TYK2 is a good strategy for the treatment of psoriasis by inhibiting the IL-23 signaling pathway.

The ATP-binding sites of members of the whole kinome tend to have a high degree of homology, among which TYK2 has a higher similarity to the ATP-binding sites of other members of the JAK family. Currently FDA-approved all JAK family kinase inhibitors, including Tofacitinib, can act on the ATP-binding pocket of TYK2, and can also bind well to JAK1, 2, and 3 isoforms. Although the inhibition of the activity of other isoforms such as JAK1, JAK2 and JAK3 by these inhibitors enhances their efficacy, they also lead to more serious side effects, including infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Since JAK2 activity is related to erythrocyte differentiation and lipid metabolism, the above-mentioned adverse reactions such as anemia are thought to be related to the insufficient selectivity of tofacitinib for JAK2, which is caused by the non-selective inhibition of the drug. Therefore, ATP-competitive TYK2 inhibitors have severely limited their clinical use due to their severe side effects. Finding a small molecule inhibitor with a new binding mode and highly selective specificity of TYK2 can effectively improve the therapeutic window of the drug, thereby improving its clinical use.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a polycyclic compound which can be used as a TYK2 inhibitor and its preparation method and use.

The present invention provides the compound represented by formula I, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate:

in,

L is a linker of 1-20 atoms; the linker is independently selected from -O-, -S-, -NR ^a -, -CR ^c R ^d -, -S(=O)-, -S(=O ) ₂ -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR ^a -, -OC(=O)NR ^a -, - NR ^a C(=O)NR ^b -, -NR ^b C(=O)-, -NR ^b C(=O)O-,

alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocycloalkyl, aryl, or heteroaryl is independently substituted with zero, one, or more ^Ra ; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl two R ^a on the same carbon atom or adjacent carbon atoms in a radical or heteroaryl group form an epoxy group, a cycloalkyl group, a heterocycloalkyl group,

Z ₁ and Z ₂ are independently selected from -O-, -S- or -NR _Z -;

R _Z is selected from hydrogen or alkyl;

L ₁ and L ₂ are independently selected from alkyl or alkyl substituted by one or more ^RL ;

R ^L is independently selected from halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS (=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R, -OC(=O)R ^a , -C(=O)OR ^b , -C(= O) ^NRcRd ,-OC(=O) ^NRcRd , ^-NRbC (=O ⁾ ^NRcRd , ^-NRbC ⁽ =O) ^Ra , ^-NRbC ⁽ =O) OR ^b , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two ^RLs of the same carbon atom form a ring oxy, cycloalkyl or heterocycloalkyl; or two R ^L of two adjacent carbon atoms form cycloalkyl or heterocycloalkyl;

R ₁ is selected from hydrogen, alkyl or haloalkyl;

Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

is a single bond or a double bond;

R ^A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , - NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O )OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O) R ^a , -NR ^b C(=O)OR ^b , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R ^A1 ; or each alkyl, alkenyl, alkynyl, cycloalkane group, heterocycloalkyl, aryl or heteroaryl, two R ^A1 on the same carbon atom or adjacent carbon atoms form epoxy, cycloalkyl, heterocycloalkyl,

n is an integer of 0, 1, 2, 3 or 4;

R ₂ , R ₃ , R ^A1 are independently selected from hydrogen, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(= O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or the same Two R ^A1 on carbon atoms form =O, cycloalkyl or heterocycloalkyl;

R ^a is independently selected from alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkene group, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl independently consisting of one or more halogen, -CN, -OH, -OMe, _-NH2 , -C(=O)Me, -COOH, -COOMe, alkyl or haloalkyl substitution;

R ^b is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl independently consisting of one or more halogen, -CN, -OH, -Me, _-NH2 , -C(=O) Me, -COOH, -COOMe, alkyl or haloalkyl substitution;

R ^c and R ^d are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is independently composed of one or more halogen, -CN, -OH, -Me, _-NH2 , -C( =O) Me, -COOH, -COOMe, alkyl or haloalkyl substitution; or a heterocycloalkyl group consisting of R ^c and R ^d and a nitrogen atom, the heterocycloalkyl group consisting of halogen, -CN, -OH, -Me , _-NH2 , -C(=O)Me, -COOH, -COOMe, alkyl or haloalkyl substituted.

further,

C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl independently consists of zero, One or more ^Ra substitutions; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is formed by two ^Ra on the same or adjacent carbon atoms Epoxy, cycloalkyl, heterocycloalkyl,

Z ₁ and Z ₂ are independently selected from -O-, -S- or -NR _Z -;

R _Z is selected from hydrogen or C ₁ -C ₆ alkyl;

L ₁ and L ₂ are independently selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more ^RL ;

R ^L is independently selected from halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS (=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R, -OC(=O)R ^a , -C(=O)OR ^b , -C(= O) ^NRcRd ,-OC(=O) ^NRcRd , ^-NRbC (=O ⁾ ^NRcRd , ^-NRbC ⁽ =O) ^Ra , ^-NRbC ⁽ =O) OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R ^L of the same carbon atom form epoxy, cycloalkyl or heterocycloalkyl; or two adjacent carbon atoms Two R ^L form a cycloalkyl or heterocycloalkyl;

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

is a single bond or a double bond;

R ^A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , - NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O )OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O) R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ Alkenyl, C2 _- _C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R ^A1 ; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is on the same or adjacent carbon atoms Two R ^A1 on the atom form epoxy, cycloalkyl, heterocycloalkyl,

n is an integer of 0, 1, 2, 3 or 4;

R ₂ , R ₃ , R ^A1 are independently selected from hydrogen, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(= O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R ^A1 on the same carbon atom form =O, cycloalkyl or heterocycloalkyl ;

R ^a is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ ~C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl _; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl independently composed of one or more halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -COOH, -COOMe, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkane base substitution;

R ^b is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C2 _- _C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl Aryl independently consists of one or more halogens, -CN, -OH, -Me, -NH ₂ , -C(=O)Me, -COOH, -COOMe, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substitution;

R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ Alkenyl, C2 _- _C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl The radical or heteroaryl is independently composed of one or more halogen, -CN, -OH, -Me, _-NH2 , -C(=O)Me, -COOH, -COOMe, _C1 - _C6 alkyl or C ₁ -C ₆ haloalkyl substitution; or a heterocycloalkyl group consisting of R ^c and R ^d and a nitrogen atom, the heterocycloalkyl group is composed of halogen, -CN, -OH, -Me, -NH ₂ , -C(=O ) Me, -COOH, -COOMe, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substitution.

further,

L is a linker of 1-10 atoms, and the linker is independently selected from -O-, -S-, -NR ^a -, -CR ^c R ^d -, -S(=O)-, -S(=O ) ₂ -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR ^a -, -OC(=O)NR ^a -, - NR ^a C(=O)NR ^b -, -NR ^b C(=O)-, -NR ^b C(=O)O-,

C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl independently consists of zero, One or more ^Ra substitutions; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is formed by two ^Ra on the same or adjacent carbon atoms

Cycloalkyl, Heterocycloalkyl,

Z ₁ and Z ₂ are independently selected from -O-, -S- or -NR _Z -;

R _Z is selected from hydrogen or C ₁ -C ₆ alkyl;

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

is a single bond or a double bond;

R ^A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , - NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O )OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O) R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ Alkenyl, C2 _- _C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R ^A1 ; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is on the same or adjacent carbon atoms Two R ^A1s on an atom form

Cycloalkyl, Heterocycloalkyl,

n is an integer of 0, 1, 2, 3 or 4;

further,

L is selected from

Z ₁ and Z ₂ are independently selected from -O-, -S- or -NR _Z -;

R _Z is selected from hydrogen or C ₁ -C ₆ alkyl;

Preferably, Z ₁ and Z ₂ are independently selected from -O- or -NR _Z -; R _Z is selected from hydrogen or C ₁ -C ₆ alkyl; L ₁ and L ₂ are independently selected from C ₁ -C ₆ alkane base;

More preferably, Z ₁ and Z ₂ are independently selected from -O- or -NR _Z -; R _Z is selected from hydrogen; L ₁ and L ₂ are independently selected from C ₁ -C ₆ alkyl groups;

Further preferably, L is selected from

further,

Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-one, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, indazole base, azaindolyl, benzimidazolyl, benzotriazaazolyl, benzofuranyl, benzothiazolebenzoxazolyl, benzisoxazolyl, benzothienyl, naphthyl.

further,

R ^A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , - NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O )OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O) R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ Alkenyl, C2- _C6alkynyl , _3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; wherein each alkyl, alkenyl, alkynyl, 3- 6-membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl independently substituted by one or more R ^A1 ; or each alkyl, alkenyl, alkynyl, 3-6 membered cycloalkane two RAs on the same carbon atom of pyrrolidinyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl form ^a 3-6 membered epoxy group, a 3-6 membered cycloalkyl group or a pyrrolidinyl group; or adjacent Two ^RAs on carbon atoms form 3-6 membered cycloalkyl or pyrrolidinyl;

R ₂ , R ₃ , R ^A1 are independently selected from hydrogen, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(= O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; or two R ^A1 on the same carbon atom form =O, 3-6 membered cycloalkyl or pyrrolidinyl;

R ^a is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ ~C alkynyl, _3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; wherein each alkyl, alkenyl, alkynyl, 3-6 membered cycloalkyl , pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl independently consisting of one or more halogens, -CN, -OH, -OMe, _-NH2 , -C(=O)Me, -COOH, - COOMe, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substitution;

R ^b is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furyl, pyridyl or pyrimidinyl; wherein, each alkyl, alkenyl, alkynyl, 3-6 membered ring Alkyl, pyrrolidinyl, phenyl, furanyl, pyridinyl or pyrimidinyl independently consisting of one or more halogen, -CN, -OH, -Me, _-NH2 , -C(=O)Me, -COOH , -COOMe, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substitution;

R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ Alkenyl, C2- _C6alkynyl , _3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; wherein each alkyl, alkenyl, alkynyl, 3- 6-membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl independently consisting of one or more halogen, -CN, -OH, -Me, _-NH2 , -C(=O)Me , -COOH, -COOMe, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^c and R ^d and nitrogen atoms form a pyrrolidinyl group consisting of halogen, -CN, - OH, -Me, -NH ₂ , -C(=O)Me, -COOH, -COOMe, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substitution;

Preferably, the 3-6 membered epoxy group is selected from

Further, the compound is shown in formula Ia:

wherein, L, R ₁ , R ₂ , R ₃ , ^A ring, n and RA are as described above;

Alternatively, the compound is shown in formula Ib:

wherein L, R ₁ , R ₂ , R ₃ , ^A ring, n and RA are as described above.

Further, the compound is shown in formula II:

wherein, R ₁ , R ₂ , R ₃ , ^A ring, n and RA are as described above;

is a single bond or a double bond;

Preferably, the compound is shown in formula III:

wherein, A ring, n and R ^A are as previously described;

is a single bond or a double bond;

More preferably, the compound is shown in formula IV:

wherein, n and ^RA are as previously described;

X, Y are independently selected from N or CR ^B ; and X and Y are not N at the same time;

R ^B is selected from hydrogen or C ₁ -C ₆ alkyl;

is a single bond or a double bond;

Further preferably, the compound is shown in formula IVa:

wherein, n and ^RA are as previously described;

is a single bond or a double bond;

Alternatively, the compound is shown in formula IVb:

wherein, n and ^RA are as previously described;

is a single bond or a double bond;

Alternatively, the compound is shown in formula IVc:

wherein, n and ^RA are as previously described;

single or double bond.

Further, the compound is one of the following compounds:

The present invention also provides a method for preparing the aforementioned compound, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, which comprises the following steps:

The present invention also provides the use of the aforementioned compound, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, in the preparation of a TYK2 inhibitor drug; and /or, use in the preparation of a medicament for a disease related to TYK2 kinase dysfunction;

Preferably, the disease is inflammatory disease, autoimmune disease, hyperproliferative disease in mammals, cancer, bone disease, neurological disease, metabolic disease, respiratory disease and/or heart disease;

More preferably, the inflammatory and autoimmune diseases are rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease;

Further preferably, the inflammatory bowel disease is ulcerative colitis and Crohn's disease.

The present invention also provides a pharmaceutical composition, which is based on the aforementioned compound, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate. ingredients, and preparations prepared with pharmaceutically acceptable excipients or auxiliary ingredients;

Preferably, the pharmaceutically acceptable adjuvant or auxiliary component is one or more pharmaceutically acceptable carriers, diluents or excipients.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions of groups or terms provided herein apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be based on the disclosure and context. , give their meanings that those skilled in the art can give them.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The hydrogen atoms in the compounds of the present invention can be various isotopes of hydrogen, such as: protium ( ¹ H), deuterium ( ² H) or tritium ( ³ H).

The structures of the compounds described in the present invention all refer to structures that can exist stably.

The minimum and maximum carbon content of the hydrocarbon groups in the present invention are indicated by prefixes, eg, the prefix ( _Ca - _Cb )alkyl denotes any alkyl group containing "a" to "b" carbon atoms. Thus, for example, _C1 - _C6 alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms; C2 _- _C6 alkynyl refers to an alkynyl group containing 1 to 6 carbon atoms.

In the present invention, halogen is fluorine, chlorine, bromine or iodine.

In the present invention, haloalkyl, hydroxyalkyl, and aminoalkyl are halogen, hydroxy, and amino substituted alkyl groups, respectively.

In the present invention, cycloalkyl refers to a monocyclic or polycyclic carbocyclic ring without double bonds; heterocycloalkyl refers to a monocyclic or polycyclic carbocyclic ring containing at least one heteroatom without double bonds. O, S or N; Aryl refers to a monocyclic or polycyclic carbocycle containing at least one double bond; Heteroaryl refers to a monocyclic or polycyclic carbocycle containing at least one double bond and at least 1 heteroatom , the heteroatom is O, S or N; the structural formula of the epoxy group is that one carbon atom on the cycloalkyl group is replaced by an O atom.

Methods of treatment provided herein include administering to a subject a therapeutically effective amount of a compound. In one embodiment, the present invention provides methods of treating inflammatory diseases, including autoimmune diseases, in mammals. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

The compound of the present invention has a good inhibitory effect on TYK2, and can be used to treat diseases related to TYK2 kinase dysfunction, such as cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease and heart disease and other diseases. At the same time, the compound of the present invention has high selectivity for the TYK2 JH2 binding domain, is safe when used, and has few toxic and side effects. The compounds of the invention can be used for preparing TYK2 inhibitors and medicines for treating diseases related to TYK2 kinase dysfunction, and have good application prospects.

Obviously, according to the above-mentioned content of the present invention, according to the common technical knowledge and conventional means in the field, without departing from the above-mentioned basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above content of the present invention will be further described in detail below through the specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

Detailed ways

The raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products, or can be synthesized by adopting or following methods known in the art.

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 Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was four Methylsilane (TMS).

An Agilent 1200 Infinity Series mass spectrometer was used for LC-MS determination.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of TLC is 0.15mm~0.20mm, and the size of TLC separation and purification products is 0.4mm~0.5mm. Thin-layer chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring and in a dry nitrogen atmosphere, the solvents are all dry, and the temperature is in degrees Celsius.

Example 1, (1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diazo Hetero-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ia-1 ) preparation

The first step: the preparation of 4-bromomethyl-1-methoxy-2-nitrobenzene

4-methyl-1-methoxy-2-nitrobenzene (5.0g, 30mmol), N-bromosuccinimide (5.3g, 30.0mmol), azobisisobutylcyanide (0.5g, 3 mmol), mixed in carbon tetrachloride (50.0 mL), reacted at 80°C for 8 h, cooled to room temperature, concentrated under reduced pressure, and then column chromatographed to obtain the compound 4-bromomethyl-1-methoxy-2-nitrobenzene (5.6 g, 77% yield).

Step 2: Preparation of 2-(N-Boc-amino)propyl-(4-methoxy-3-nitrobenzyl)ether

4-Bromomethyl-1-methoxy-2-nitrobenzene (1.4 g, 5.7 mmol), N-Boc-DL alaninol (1.0 g, 5.7 mmol), mixed in N,N-dimethyl In formamide (20.0 mL), sodium hydride (content 60%) (0.5 g, 11.7 mmol) was added at zero temperature, and the reaction was carried out at room temperature for 4.0 h. The reaction solution was added with 100.0 mL of ethyl acetate and 50.0 mL of water, and the layers were separated, and the organic phase was separated. And washed with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography gave the compound 2-(N-Boc-amino)propyl-(4-methoxy-3-nitrobenzyl) base) ether (1.2 g, 43% yield).

MS m/z(ESI): 241.2[M+H-100] ⁺ .

The third step: preparation of 2-aminopropyl-(4-methoxy-3-nitrobenzyl) ether

2-(N-Boc-amino)propyl-(4-methoxy-3-nitrobenzyl)ether (1.2 g, 3.5 mmol), dichloromethane (24.0 mL), trifluoroacetic acid (12.0 mL) , mixed in a 100mL single-neck flask, reacted at room temperature for 2h, concentrated under reduced pressure, the residue was added with ethyl acetate (100.0mL), water (50.0mL), and the liquids were separated. The phase was extracted with dichloromethane/methanol=10/1 (v/v), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound 2-aminopropyl- (4-Methoxy-3-nitrobenzyl) ether (0.6 g, 71% yield).

MS m/z(ESI): 241.2[M+H] ⁺ .

The fourth step: the preparation of 2-(2-(N-Boc-amino) ethyl) dimethyl malonate

Dimethyl malonate (5.0g, 38.0mmol), tetrahydrofuran (50.0mL) were added in a 250mL there-necked flask, cooled to 0°C, sodium hydride (60%, 1.5g, 38.0mmol) was added in batches, and the reaction was performed at 0°C For 30 minutes, N-BOC-bromoethylamine (8.4 g, 38.0 mmol) was added to the reaction solution, reacted at room temperature overnight, cooled to 0° C., water (10.0 mL) was added dropwise to quench the reaction, and the reaction solution was washed with ethyl acetate (150.0 mL) and water (50.0 mL) were separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and column chromatography to obtain compound 2-(2-(N-Boc- Dimethyl amino)ethyl)malonate (3.4 g, 33% yield).

MS m/z(ESI): 276.2[M+H] ⁺ .

The fifth step: preparation of 6-(2-(N-Boc-aminoethyl))-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester

Dimethyl 2-(2-(N-Boc-amino)ethyl)malonate (1.5g, 5.5mmol), 3-amino-4-ethoxycarbonylpyrazole (0.6g, 3.4mmol), tert-butyl Potassium alkoxide (0.8g, 7.3mmol) was mixed in ethanol (12.0mL), reacted at 80°C overnight, cooled to room temperature, the reaction solution was adjusted to pH=2 with 1mol/L hydrochloric acid, and the filter cake was collected after filtration to obtain compound 6- (2-(N-Boc-aminoethyl))-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (0.4 g, 31% yield).

MS m/z(ESI): 367.0[M+H] ⁺ .

Step 6: Preparation of ethyl 5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylate

Ethyl 6-(2-(N-Boc-aminoethyl))-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.5 g, 1.4 mmol), trichloro Phosphorus oxide (5.0 mL) was added to a 50 mL single-neck flask, reacted at 110°C for 20.0 h, cooled to room temperature, concentrated under reduced pressure, the residue was poured into ice water, adjusted to pH=8.0 with saturated aqueous sodium bicarbonate solution, and acetic acid was added to the residue Ethyl ester (50.0 mL), water (20.0 mL) were separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (dichloromethane: methanol =20:1), the compound 5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid ethyl ester (70.0 mg, the yield was 19%).

MS m/z(ESI): 267.0, 269.1[M+H] ⁺ .

Step 7: Preparation of 5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid

Ethyl 5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylate (80.0 mg, 0.3 mmol), 1N hydrogen Aqueous sodium oxide solution (1.0 mL), methanol (2.0 mL), stirred at room temperature for 2.0 h, adjusted to pH=7.0 with 1N hydrochloric acid, extracted with dichloromethane, and concentrated to obtain compound 5-chloro-7,8-dihydro-6H-pyrazole Hepo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (70.0 mg, 98% yield).

MS m/z(ESI): 239.1[M+H] ⁺ .

Step 8: 5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H-pyrazole Preparation of [1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (70.0 mg, 0.3 mmol), 2-aminopropane yl-(4-methoxy-3-nitrobenzyl) ether (180.0 mg, 0.8 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole -1-yl) urea hexafluorophosphate (304.0 mg, 0.8 mmol) was mixed with N,N-dimethylformamide (4.0 mL), the reaction was stirred at room temperature for 2.0 h, cooled to room temperature, concentrated under reduced pressure, and subjected to column chromatography. The compound 5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H-pyrazolo[ 1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (110.0 mg, 80% yield).

MS m/z(ESI): 461.3,463.2[M+H] ⁺ .

Step 9: 5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-N-Boc-7,8-dihydro- Preparation of 6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H-pyrazolo[1, 5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (70.0mg, 0.15mmol), di-tert-butyl dicarbonate (39.0mg, 0.18mmol), triethylamine (46.0mg, 0.45mmol) ), 4-dimethylaminopyridine (2.0mg, 0.02mmol), mixed in (dichloromethane 5.0mL), reacted at room temperature for 0.5 hours, the reaction solution was separated with dichloromethane (50.0mL) and water (20.0mL) , the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound 5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl yl)oxy)prop-2-yl)-N-Boc-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (90.0 mg, crude).

MS m/z(ESI): 561.2,563.2[M+H] ⁺ .

Step 10: 5-Chloro-N-(1-(((4-methoxy-3-aminobenzyl)oxy)propan-2-yl)-N-Boc-7,8-dihydro-6H - Preparation of pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-N-Boc-7,8-dihydro-6H-pyrazole Io[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (90.0 mg, crude), iron powder (90.0 mg, 1.6 mmol), ammonium chloride (85.0 mg, 1.6 mmol) , water (1.0 mL), mixed in ethanol (5.0 mL), reacted at 60°C for 1.0 h, cooled to room temperature, filtered under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was washed with ethyl acetate (50.0 mL) and water ( 20.0 mL) was separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 5-chloro-N-(1-((((4-methoxyl -3-Aminobenzyl)oxy)prop-2-yl)-N-Boc-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine -3-Carboxamide (70.0 mg, crude).

MS m/z(ESI): 531.2,533.2[M+H] ⁺ .

The eleventh step: (1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-di Aza-N-Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9- Preparation of ketones

5-Chloro-N-(1-(((4-methoxy-3-aminobenzyl)oxy)prop-2-yl)-N-Boc-7,8-dihydro-6H-pyrazolo [1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (70.0 mg, 0.13 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6 '-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0 mg, 0.02 mmol), cesium carbonate (86.0 mg, 0.26 mmol), mixed in 1,4-dioxane (14.0 mL), the reaction system was replaced with nitrogen three times, reacted at 80°C overnight, cooled to room temperature, concentrated under reduced pressure, and the compound ( ¹³⁾ was obtained after column chromatography. E,14E)-36 ^- methoxy- ⁷ -methyl- ^17,18 -dihydro-16H- ⁵ -oxa-2,8-diaza ^- N-Boc-1 (5,3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (51.0 mg, the yield was 78%).

MS m/z(ESI): 495.2[M+H] ⁺ .

The twelfth step: ( ^13E , ^14E )-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2,8-di Aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ia- 1) Preparation

(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza-N- Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (5.0 mg, 0.01 mmol), ethanolic hydrochloric acid solution (15%) (0.1 mL), ethyl acetate (0.1 mL), were added to a 4 mL bottle, reacted at room temperature for 5.0 h, adjusted to pH=8.0 with saturated aqueous sodium bicarbonate solution at 0°C, The residue was separated with ethyl acetate (30.0 mL) and water (10.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to prepare compound (1) ^3E ,14E)-36 ^- methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2,8-diaza-1(5, 3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ia-1) (2.0 mg, received rate of 50%).

MS m/z(ESI): 395.0[M+H]+.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.08(s,1H), 8.32(d,2H), 8.25(t,1H), 8.15(s,1H), 6.94(d,1H), 6.77( d, 1H), 4.52(dd, 2H), 3.94(dd, 1H), 3.86(s, 3H), 3.83(t, 2H), 3.49(d, 1H), 3.41(dd, 1H), 3.25–3.13 (m, 2H), 1.14(d, 3H).

Example 2, (1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3)- Preparation of Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-1)

The first step: (1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3)- Preparation of Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-1)

(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza-N- Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (15.0 mg, 0.03 mmol), manganese dioxide (52.0 mg, 0.6 mmol), mixed in toluene (1.5 mL), reacted at 80 ° C for 24 h, cooled to room temperature, filtered under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was washed with ethyl acetate The organic phase was separated and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative plate to obtain the title compound ( ^13E , ^14E )-36 ^- methoxy -7-Methyl-18H- ⁵ -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine -3(1,3)-Benzylcyclononyl-9-one (Ib-1) (7.0 mg, 58%).

MS m/z(ESI): 393.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ12.95(s,1H), 9.07(s,1H), 8.36(d,2H), 8.28-8.23(m,2H), 8.18(s,1H), 6.93(d,1H),6.77(d,1H),4.57(dd,2H),3.96(dd,1H),3.86(s,3H),3.48(d,1H),3.45(dd,1H),1.16 (d,3H).

Example ³ , (S)-(13E, ^14E )-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2, 8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one Preparation of (Ia-9)

The first step: preparation of (S)-2-(N-Boc-amino)propyl-(4-methoxy-3-nitrobenzyl) ether

4-Bromomethyl-1-methoxy-2-nitrobenzene (2.0 g, 8.2 mmol), (S)-N-tert-butoxycarbonyl-alaninol (1.4 g, 8.2 mmol), mixed in N , N-dimethylformamide (30.0 mL), sodium hydride (content 60%) (0.7 g, 16.7 mmol) was added at zero temperature, the reaction was carried out at room temperature for 4.0 h, 100.0 mL of ethyl acetate and 50.0 mL of water were added to the reaction solution, Separation, separating the organic phase and washing with saturated aqueous sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound (S)-2-(N-tert-butoxycarbonyl-amino)propyl group by column chromatography -(4-Methoxy-3-nitrobenzyl) ether (1.7 g, 61% yield).

MS m/z(ESI): 241.2[M+H-100] ⁺ .

The second step: the preparation of (S)-2-aminopropyl-(4-methoxy-3-nitrobenzyl) ether

(S)-2-(N-tert-butoxycarbonyl-amino)propyl-(4-methoxy-3-nitrobenzyl)ether (1.7 g, 5.0 mmol), dichloromethane (30.0 mL), Trifluoroacetic acid (15.0 mL) was mixed in a 100 mL single-necked flask, reacted at room temperature for 2.0 h, concentrated under reduced pressure, added ethyl acetate (100.0 mL) and water (50.0 mL) to the residue, and separated the aqueous phase with saturated hydrogen carbonate. Aqueous sodium solution was adjusted to pH=9.0, the aqueous phase was extracted with dichloromethane/methanol=10/1 (v/v), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound (S)-2-aminopropyl-(4-methoxy-3-nitrobenzyl) ether (0.9 g, yield 73%) was obtained.

MS m/z(ESI): 241.2[M+H] ⁺ .

The third step: (S)-5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro- Preparation of 6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (100.0 mg, 0.4 mmol), (S)- 2-Aminopropyl-(4-methoxy-3-nitrobenzyl) ether (257.0 mg, 1.1 mmol), N,N,N',N'-tetramethyl-O-(7-aza Benzotriazol-1-yl)urea hexafluorophosphate (425.0 mg, 1.1 mmol) was mixed with N,N-dimethylformamide (4.0 mL), stirred at room temperature for 2.0 h, cooled to room temperature, and concentrated under reduced pressure , column chromatography to obtain compound (S)-5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl)-7,8-di Hydrogen-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (170.0 mg, 88% yield).

MS m/z(ESI): 461.3,463.2[M+H] ⁺ .

The fourth step: (S)-5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-N-tert-butoxycarbonyl- Preparation of 7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

(S)-5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H-pyrazole Lo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (85.0 mg, 0.2 mmol), di-tert-butyl dicarbonate (44.0 mg, 0.2 mmol), triethylamine (60.0 mg, 0.6 mmol), 4-dimethylaminopyridine (2.0 mg, 0.02 mmol), mixed in dichloromethane (5.0 mL), and reacted at room temperature for 0.5 hours, the reaction solution was mixed with dichloromethane (50.0 mL) and water (20.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound (S)-5-chloro-N-(1-((((4-methyl) Oxy-3-nitrobenzyl)oxy)prop-2-yl)-N-tert-butoxycarbonyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3 ,2-e]pyrimidine-3-carboxamide (95.0 mg, crude).

MS m/z(ESI): 561.2,563.2[M+H] ⁺ .

The fifth step: (S)-5-chloro-N-(1-(((4-methoxy-3-aminobenzyl)oxy)propan-2-yl)-N-tert-butoxycarbonyl-7 Preparation of ,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

(S)-5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-N-Boc-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (95.0mg, crude), iron powder (95.0mg, 1.7mmol), ammonium chloride (90.0mg , 1.7 mmol), water (1.0 mL), mixed in ethanol (5.0 mL), reacted at 60°C for 1.0 h, cooled to room temperature, filtered under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was washed with ethyl acetate (50.0 mL). ) and water (20.0 mL) were separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (S)-5-chloro-N-(1- (((4-Methoxy-3-aminobenzyl)oxy)prop-2-yl)-N-Boc-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo [3,2-e]pyrimidine-3-carboxamide (73.0 mg, crude).

MS m/z(ESI): 531.2,533.2[M+H] ⁺ .

The sixth step: ( ^S ) ^- (13E,14E)-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2, 8-Diaza-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzo Preparation of cyclononyl-9-one

(S)-5-Chloro-N-(1-(((4-methoxy-3-aminobenzyl)oxy)propan-2-yl)-N-Boc-7,8-dihydro-6H - Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (73.0 mg, 0.14 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2', 4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0 mg, 0.02 mmol), Cesium carbonate (91.0 mg, 0.28 mmol) was mixed in 1,4-dioxane (14.0 mL), the reaction system was replaced with nitrogen three times, reacted at 80°C overnight, cooled to room temperature, concentrated under reduced pressure, and obtained after column chromatography Compound ( ^S ) ^- (13E,14E)-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2,8-di Aza-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl -9-one (45.0 mg, 66% yield).

MS m/z(ESI): 495.2[M+H] ⁺ .

The seventh step: ( ^S ) ^- (13E,14E)-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2, 8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one Preparation of (Ia-9)

(S)-(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza Hetero-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl- 9-ketone (10.0 mg, 0.01 mmol), ethanolic hydrochloric acid solution (15%) (0.1 mL), ethyl acetate (0.1 mL), were added to a 4 mL bottle, reacted at room temperature for 5.0 h, and saturated bicarbonate at 0°C Aqueous sodium solution was adjusted to pH=8.0. The residue was separated with ethyl acetate (30.0 mL) and water (10.0 mL). The organic phase was separated and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound (S)-(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2 was isolated by preparative plate ,8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9- Ketone (Ia-9) (5.0 mg, 50% yield).

MS m/z(ESI): 395.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s,1H), 8.35(d,2H), 8.24(t,1H), 8.15(s,1H), 6.97(d,1H), 6.77( d, 1H), 4.55(dd, 2H), 3.94(dd, 1H), 3.86(s, 3H), 3.83(t, 2H), 3.47(d, 1H), 3.42(dd, 1H), 3.25–3.16 (m, 2H), 1.14(d, 3H).

Example 4, (S)-(1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5 Preparation of ,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-7)

The first step: (S)-(1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5 Preparation of ,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-7)

(S)-(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza Hetero-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl- 9-keto (10.0mg, 0.02mmol), manganese dioxide (34.0mg, 0.4mmol), mixed in toluene (1.5mL), reacted at 80°C for 24.0h, cooled to room temperature, filtered under reduced pressure, and the filter cake was washed with ethyl acetate Ester wash, the filtrate was separated with ethyl acetate and water, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by preparative plate to obtain the title compound (S)-(1 ³ E , 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5- a] Pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-7) (5.0 mg, 62%).

MS m/z(ESI): 393.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ12.35(s,1H), 9.07(s,1H), 8.35(d,2H), 8.29-8.26(m,2H), 8.18(s,1H), 6.93(d,1H),6.77(d,1H),4.52(dd,2H),3.96(dd,1H),3.87(s,3H),3.48(d,1H),3.42(dd,1H),1.14 (d,3H).

Example 5, (R)-(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2, 8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one Preparation of (Ia-8)

The first step: preparation of (R)-2-(N-tert-butoxycarbonyl-amino)propyl-(4-methoxy-3-nitrobenzyl) ether

4-Bromomethyl-1-methoxy-2-nitrobenzene (2.0 g, 8.2 mmol), (R)-N-tert-butoxycarbonyl-alaninol (1.4 g, 8.2 mmol), mixed in N , N-dimethylformamide (30.0 mL), sodium hydride (content 60%) (0.7 g, 16.7 mmol) was added at zero temperature, the reaction was carried out at room temperature for 4.0 h, 100.0 mL of ethyl acetate and 50.0 mL of water were added to the reaction solution, Separation, separating the organic phase and washing with saturated aqueous sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound (R)-2-(N-tert-butoxycarbonyl-amino)propyl group by column chromatography -(4-Methoxy-3-nitrobenzyl) ether (1.6 g, 57% yield).

MS m/z(ESI): 241.2[M+H-100] ⁺ .

The second step: preparation of (R)-2-aminopropyl-(4-methoxy-3-nitrobenzyl) ether

(R)-2-(N-tert-butoxycarbonyl-amino)propyl-(4-methoxy-3-nitrobenzyl)ether (1.6 g, 4.7 mmol), dichloromethane (30.0 mL), Trifluoroacetic acid (15.0 mL), mixed in a 100 mL single-necked flask, reacted at room temperature for 2 h, concentrated under reduced pressure, added ethyl acetate (100.0 mL) and water (50.0 mL) to the residue, and separated the aqueous phase with saturated sodium bicarbonate. The aqueous solution was adjusted to pH=9.0, the aqueous phase was extracted with dichloromethane/methanol=10/1 (v/v), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound (R)-2-aminopropyl-(4-methoxy-3-nitrobenzyl) ether (0.7 g, 62% yield).

MS m/z(ESI): 241.2[M+H] ⁺ .

The third step: (R)-5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro- Preparation of 6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (70.0 mg, 0.3 mmol), (R)- 2-Aminopropyl-(4-methoxy-3-nitrobenzyl) ether (180.0 mg, 0.8 mmol), N,N,N',N'-tetramethyl-O-(7-aza Benzotriazol-1-yl)urea hexafluorophosphate (304.0 mg, 0.8 mmol) was mixed with N,N-dimethylformamide (4.0 mL), stirred at room temperature for 2.0 h, cooled to room temperature, and concentrated under reduced pressure , column chromatography to obtain compound (R)-5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl)-7,8-di Hydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (110.0 mg, 80% yield).

MS m/z(ESI): 461.3,463.2[M+H] ⁺ .

The fourth step: (R)-5-chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl)-N-Boc-7,8 Preparation of -dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

(R)-5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H-pyrazole Lo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (70.0 mg, 0.15 mmol), di-tert-butyl dicarbonate (39.0 mg, 0.18 mmol), triethylamine (46.0 mg, 0.45 mmol), 4-dimethylaminopyridine (2.0 mg, 0.02 mmol), mixed in (dichloromethane 5.0 mL), and reacted at room temperature for 0.5 hour, the reaction solution was mixed with dichloromethane (50.0 mL) and water (20.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound (R)-5-chloro-N-(1-((((4-methyl) Oxy-3-nitrobenzyl)oxy)prop-2-yl)-N-tert-butoxycarbonyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3 ,2-e]pyrimidine-3-carboxamide (95.0 mg, crude).

MS m/z(ESI): 561.2,563.2[M+H] ⁺ .

The fifth step: (R)-5-chloro-N-(1-(((4-methoxy-3-aminobenzyl)oxy)propan-2-yl)-N-tert-butoxycarbonyl-7 Preparation of ,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

(R)-5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-N-tert-butoxycarbonyl-7,8- Dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (90.0 mg, crude), iron powder (90.0 mg, 1.6 mmol), ammonium chloride (85.0 mg, 1.6 mmol), water (1.0 mL), mixed in ethanol (5.0 mL), reacted at 60°C for 1.0 h, cooled to room temperature, filtered under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was washed with ethyl acetate (50.0 mL) and water (20.0 mL) were separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (R)-5-chloro-N- (1-(((4-Methoxy-3-aminobenzyl)oxy)prop-2-yl)-N-tert-butoxycarbonyl-7,8-dihydro-6H-pyrazolo[1, 5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (75.0 mg, crude).

MS m/z(ESI): 531.2,533.2[M+H] ⁺ .

The sixth step: ( ^R ) ^- (13E,14E)-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2, 8-Diaza-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzo Preparation of cyclononyl-9-one

(R)-5-Chloro-N-(1-(((4-methoxy-3-aminobenzyl)oxy)prop-2-yl)-N-tert-butoxycarbonyl-7,8-di Hydrogen-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (70.0 mg, 0.13 mmol), methanesulfonic acid (2-di-tert-butylphosphino- 2',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0 mg, 0.02 mmol), cesium carbonate (86.0 mg, 0.26 mmol), mixed in 1,4-dioxane (14.0 mL), the reaction system was replaced with nitrogen three times, reacted at 80° C. overnight, cooled to room temperature, concentrated under reduced pressure, and the column layer Compound ( ^R ) ^- (13E,14E)-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2 was obtained after precipitation, 8-Diaza-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzo Cyclononyl-9-one (45.0 mg, 69% yield).

MS m/z(ESI): 495.2[M+H] ⁺ .

The seventh step: ( ^R ) ^- (13E,14E)-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2, 8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one Preparation of (Ia-8)

(R)-(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza Hetero-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl- 9-keto (10.0 mg, 0.01 mmol), ethanolic hydrochloric acid solution (15%) (0.2 mL), ethyl acetate (0.2 mL), were added to a 4 mL bottle, reacted at room temperature for 5.0 h, and saturated bicarbonate at 0°C Aqueous sodium solution was adjusted to pH=8.0. The residue was separated with ethyl acetate (30.0 mL) and water (10.0 mL). The organic phase was separated and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound (R)-(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2 was isolated by preparative plate ,8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9- Ketone (Ia-8) (4.0 mg, 50% yield).

MS m/z(ESI): 395.0[M+H]+.

¹ H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.33(d,2H),8.24(t,1H),8.15(s,1H),6.95(d,1H),6.77(d ,1H),4.51(dd,2H),3.94(dd,1H),3.86(s,3H),3.83(t,2H),3.49(d,1H),3.42(dd,1H),3.25–3.12( m,2H),1.12(d,3H).

Example 6, (R)-(1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5 Preparation of ,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-3)

The first step: (R)-(1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5 Preparation of ,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-3)

(R)-(1 ³ E,1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza Hetero-N-tert-butoxycarbonyl-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl- 9-keto (10.0 mg, 0.02 mmol), manganese dioxide (34.0 mg, 0.4 mmol), mixed in toluene (2.0 mL), reacted at 80 ° C for 24 h, cooled to room temperature, filtered under reduced pressure, and the filter cake was washed with ethyl acetate Washed, the filtrate was separated with ethyl acetate and water, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by preparative plate to obtain the title compound (R)-(1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a ]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-3) (6.0 mg, 59%).

MS m/z(ESI): 393.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ12.88(s,1H), 9.05(s,1H), 8.35(d,2H), 8.28–8.22(m,2H), 8.18(s,1H), 6.98(d,1H),6.76(d,1H),4.52(dd,2H),3.94(dd,1H),3.89(s,3H),3.48(d,1H),3.41(dd,1H),1.13 (d,3H).

Example 7, (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -fluoro-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza Hetero-1(5,3)-pyrazo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-benzocyclononan-9-one (Ia-6) preparation

The first step: 1-(bromomethyl)-3-fluoro-5-nitrobenzene

1-Fluoro-3-methyl-5-nitrobenzene (1.6g, 30mmol), N-bromosuccinimide (1.8g, 10.0mmol), azobisisobutylcyanide (0.16g, 1.0mmol) ), mixed in carbon tetrachloride (20.0 mL), reacted at 80 °C for 16 h, cooled to room temperature, concentrated under reduced pressure, and column chromatography to obtain compound 1-(bromomethyl)-3-fluoro-5-nitrobenzene ( 1.4g, the yield is 61%).

The second step: preparation of (R)-(1-((3-fluoro-5-nitrobenzyl)oxy)prop-2-yl)carbamic acid tert-butyl ester

1-(Bromomethyl)-3-fluoro-5-nitrobenzene (1.4 g, 6.0 mmol), (R)-N-Boc-alaninol (1.1 g, 6.0 mmol), mixed in N,N- In dimethylformamide (20.0 mL), sodium hydride (content 60%) (0.24 g, 6.0 mmol) was added at zero temperature, the reaction was carried out at room temperature for 4.0 h, 100.0 mL of ethyl acetate and 50.0 mL of water were added to the reaction solution, and the liquids were separated. The organic phase was separated and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography to obtain compound (R)-(1-((3-fluoro-5-nitrobenzyl)oxygen) tert-butyl)propan-2-yl)carbamate (0.7 g, 35% yield).

MS m/z(ESI): 229.2[M+H-100] ⁺ .

The third step: preparation of (R)-(1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)amine

(R)-(1-((3-Fluoro-5-nitrobenzyl)oxy)propan-2-yl)carbamate tert-butyl ester (0.7 g, 2.1 mmol), dichloromethane (20.0 mL), Trifluoroacetic acid (10.0 mL), mixed in a 100 mL single-necked flask, reacted at room temperature for 2 h, concentrated under reduced pressure, added ethyl acetate (100.0 mL) and water (50.0 mL) to the residue, and separated the aqueous phase with saturated sodium bicarbonate. The aqueous solution was adjusted to pH=9.0, the aqueous phase was extracted with dichloromethane/methanol=10/1 (v/v), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound (R)-2-aminopropyl-(4-methoxy-3-nitrobenzyl)ether (0.3 g, 61% yield).

MS m/z(ESI): 229.2[M+H] ⁺ .

The fourth step: ((R)-5-chloro-N-(1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)-7,8-dihydro-6H- Preparation of Pyrazole[1,5-a]pyrrole[3,2-e]pyrimidine-3-carboxamide

5-Chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (70.0 mg, 0.3 mmol), (R)- 2-Aminopropyl-(4-methoxy-3-nitrobenzyl) ether (67.0 mg, 0.3 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6' -Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (114.0 mg, 0.3 mmol), N,N-diphenyl Isopropylethylamine (116 mg, 0.9 mmol) was mixed with N,N-dimethylformamide (4.0 mL), the reaction was stirred at room temperature for 2.0 h, cooled to room temperature, concentrated under reduced pressure, and subjected to column chromatography to obtain compound ((R )-5-chloro-N-(1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)-7,8-dihydro-6H-pyrazolo[1,5- a] Pyrro[3,2-e]pyrimidine-3-carboxamide (101.0 mg, 74% yield).

MS m/z(ESI): 449.3,451.2[M+H] ⁺ .

The fifth step: tert-butyl (R)-5-chloro-3-((1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)carbamoyl)-6, Preparation of 7-dihydro-8H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-8-carboxylate

(R)-5-Chloro-N-(1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)-7,8-dihydro-6H-pyrazole[1, 5-a]pyrrole[3,2-e]pyrimidine-3-carboxamide (45.0mg, 0.1mmol), di-tert-butyl dicarbonate (22mg, 0.1mmol), triethylamine (30.0mg, 0.3mmol), 4-Dimethylaminopyridine (2.0 mg, 0.02 mmol) was mixed in (dichloromethane 5.0 mL), reacted at room temperature for 0.5 hour, the reaction solution was separated with dichloromethane (30.0 mL) and water (20.0 mL), and separated The organic phase was washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound tert-butyl(R)-5-chloro-3-((1-((3-fluoro-5- Nitrobenzyl)oxy)propan-2-yl)carbamoyl)-6,7-dihydro-8H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-8-carboxylate acid salt (55.0 mg, crude).

MS m/z(ESI): 549.2,551.2[M+H] ⁺ .

The sixth step: (tert-butyl(R)-3-((1-((3-amino-5-fluorobenzyl)oxy)propan-2-yl)carbamoyl)-5-chloro-6, Preparation of 7-dihydro-8H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-8-carboxylate

(R)-5-Chloro-3-((1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)carbamoyl)-6,7-dihydro-8H- Pyrazole[1,5-a]pyrrole[3,2-e]pyrimidine-8-carboxylate (55.0mg, crude), iron powder (56.0mg, 1.0mmol), ammonium chloride (53.0mg, 1.0mmol) ), water (1.0 mL), mixed in ethanol (5.0 mL), reacted at 60°C for 1.0 h, cooled to room temperature, filtered under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was washed with ethyl acetate (30.0 mL) and water (20.0 mL) was separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound tert-butyl(R)-3-((1-((3 -Amino-5-fluorobenzyl)oxy)propan-2-yl)carbamoyl)-5-chloro-6,7-dihydro-8H-pyrazolo[1,5-a]pyrrole[3,2 -e] Pyrimidine-8-carboxylate (50.0 mg, crude).

MS m/z(ESI): 519.2,521.2[M+H] ⁺ .

The seventh step: tert-butyl (R)-(1 ³ E, 1 ⁴ E)-3 ⁵ -fluoro-7-methyl-9-oxo-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5 -Oxo-2,8-diazo-1(5,3)-pyrazo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-phenylcyclononane-1 Preparation of ⁸ -carboxylate

(R)-3-((1-((3-Amino-5-fluorobenzyl)oxy)propan-2-yl)carbamoyl)-5-chloro-6,7-dihydro-8H-pyridine Azole[1,5-a]pyrro[3,2-e]pyrimidine-8-carboxylate (50.0 mg, 0.1 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4', 6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0 mg, 0.02 mmol), cesium carbonate ( 65.0 mg, 0.2 mmol), mixed in 1,4-dioxane (10.0 mL), the reaction system was replaced with nitrogen three times, reacted at 80 °C overnight, cooled to room temperature, concentrated under reduced pressure, and the compound tert-butyl was obtained after column chromatography Base ( ^R ) ^- (13E,14E)-35-fluoro- ⁷ -methyl- ⁹ -oxo-17,18-dihydro-16H- ⁵ -oxo- ² , 8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrole[3,2-e]pyrimidine-3(1,3)-phenylcyclononane- ¹⁸ -carboxylate ( 26.0 mg, the yield is 53%).

MS m/z(ESI): 483.2[M+H] ⁺ .

The eighth step: (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -fluoro-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diazo Hetero-1(5,3)-pyrazo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-benzocyclononan-9-one (Ia-6) preparation

tert-Butyl( ^R ) ^- (13E,14E)-35-fluoro- ⁷ -methyl- ⁹ -oxo- ^17,18 -dihydro-16H- ⁵ -oxo- 2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-phenylcyclononane- ¹⁸ -carboxylic acid Salt (26 mg, 0.05 mmol), ethanolic hydrochloric acid solution (15%) (0.5 mL), ethyl acetate (0.5 mL), were added to a 4 mL bottle, reacted at room temperature for 5.0 h, and adjusted with saturated aqueous sodium bicarbonate solution at 0°C pH=8.0, the residue was separated with ethyl acetate (30.0 mL) and water (10.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared for plate separation The compound (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -fluoro-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8-diaza- 1(5,3)-Pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-benzocyclononan-9-one (Ia-6) (13.0 mg , the yield is 49%).

MS m/z(ESI): 383.0[M+H]+.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.09(s,1H), 8.34(d,2H), 8.22(t,1H), 8.16(s,1H), 6.91(d,1H), 6.75( d, 1H), 4.52(dd, 2H), 3.94(dd, 1H), 3.85(t, 2H), 3.48(d, 1H), 3.41(dd, 1H), 3.24–3.11(m, 2H), 1.13 (d,3H).

Example 8. (R, 1 ³ E, 1 ⁴ E)-35-fluoro-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3)-pyridine Preparation of azolo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-benzocyclononan-9-one (Ib-4)

The first step: (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -fluoro-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3)- Preparation of Pyrazo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-benzocyclononan-9-one (Ib-4)

( ^R ,13E,14E)-35-fluoro- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2,8-diaza- ¹ ( 5,3)-Pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-benzocyclononan-9-one (5.0 mg, 0.01 mmol), dioxide Manganese (22.0 mg, 0.3 mmol) was mixed in toluene (1.5 mL), reacted at 80 °C for 24 h, cooled to room temperature, filtered under reduced pressure, the filter cake was washed with ethyl acetate, the filtrate was separated with ethyl acetate and water, and the organic The phases were washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative plate to obtain the title compound (R)-(1 ³ E, 1 ⁴ E)-3 ⁶ -methoxy-7 -Methyl-18H- ⁵ -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3 (1,3)-Benzylcyclononyl-9-one (Ib-4) (2.0 mg, 40%).

MS m/z(ESI): 381.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ12.96(s,1H), 9.09(s,1H), 8.34(d,2H), 8.25-8.21(m,2H), 8.16(s,1H), 6.91(d,1H), 6.75(d,1H), 4.52(dd,2H), 3.94(dd,1H), 3.48(d,1H), 3.41(dd,1H), 1.13(d,3H).

Example 9, (R, 1 ³ E, 1 ⁴ E)-3 ² -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8- Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(3,5)-pyridocyclononyl-9-one (Ia -7) Preparation

The first step: the preparation of 5-methyl-2-methoxy-3-nitropyridine

5-methyl-3-nitro-2-chloropyridine (11.5g, 66.4mmol), sodium methoxide (7.2g, 132.8mmol), mixed in methanol (180.0mL), reacted at 60°C for 7h, cooled to room temperature, After concentration under reduced pressure, silica gel column chromatography gave the compound 5-methyl-2-methoxy-3-nitropyridine (9.0 g, yield 81.0%).

The second step: the preparation of 5-bromomethyl-2-methoxy-3-nitropyridine

5-methyl-2-methoxy-3-nitropyridine (7.1 g, 42.2 mmol), N-bromosuccinimide (9.8 g, 54.9 mmol), azobisisobutylcyanide (1.4 g , 8.4 mmol), mixed in carbon tetrachloride (105.0 mL), reacted at 80 ° C for 16 h, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and then column chromatography gave the compound 5-bromomethyl-2-methoxy- 3-Nitropyridine (5.6 g, 54.0% yield).

The third step: preparation of (R)-5-(2-(N-Boc-amino)propoxymethyl)-2-methoxy-3-nitropyridine

5-Bromomethyl-2-methoxy-3-nitropyridine (2.5 g, 10.1 mmol), (R)-1-(N-Boc-amino)-2-propanol (2.3 g, 13.2 mmol) , sodium hydride (content 60%) (0.5g, 12.1mmol), mixed in N,N-dimethylformamide (50.0mL), reacted at room temperature for 4h, the reaction solution was added with ethyl acetate (100.0mL), water ( 50.0 mL), separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and column chromatography to obtain compound (R)-5-(2-(N-Boc- Amino)propoxymethyl)-2-methoxy-3-nitropyridine (1.2 g, 35.0% yield).

MS m/z(ESI): 242.2[M+H-100] ⁺ .

The fourth step: the preparation of (R)-5-((2-aminopropoxy) methyl)-2-methoxy-3-nitropyridine

(R)-5-(2-(N-Boc-amino)propoxymethyl)-2-methoxy-3-nitropyridine (0.9 g, 2.6 mmol), dichloromethane (21.0 mL), Trifluoroacetic acid (7.0 mL) was mixed in a 50 mL single-necked flask, reacted at room temperature for 2 h, concentrated under reduced pressure, the residue was added with ethyl acetate (50.0 mL), water (50.0 mL), and the layers were separated, the organic phase was discarded, and the aqueous phase was removed. Adjust pH=9 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, separate the organic phase and wash with saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound (R)-5-( (2-Aminopropoxy)methyl)-2-methoxy-3-nitropyridine (0.4 g, 63.0% yield).

MS m/z(ESI): 242.2[M+H] ⁺ .

The fifth step: (R)-5-chloro-N-(2-((2-methoxy-3-nitropyridin-5-yl)methoxy)propyl)-7,8-dihydro- Preparation of 6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid ethyl ester (144.0 mg, 0.5 mmol), (R) -5-((2-Aminopropoxy)methyl)-2-methoxy-3-nitropyridine (260.0 mg, 1.08 mmol), 1 M solution of trimethylaluminum in tetrahydrofuran (2.7 mL, 2.7 mmol) Mixed in tetrahydrofuran (10.0 mL), stirred at 80 °C for 1 h, cooled to room temperature, concentrated under reduced pressure, and obtained compound (R)-5-chloro-N-(2-((2-methoxy-3 by column chromatography) -Nitropyridin-5-yl)methoxy)propyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-methyl Amide (90.0 mg, 39.1% yield).

MS m/z(ESI): 462.1,464.1[M+H] ⁺ .

The sixth step: (R)-5-chloro-N-(2-((2-methoxy-3-nitropyridin-5-yl)methoxy)propyl)-N-Boc-7,8 - Preparation of dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

(R)-5-Chloro-N-(2-((2-methoxy-3-nitropyridin-5-yl)methoxy)propyl)-7,8-dihydro-6H-pyrazole Lo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (140.0 mg, 0.3 mmol), di-tert-butyl dicarbonate (71.0 mg, 0.3 mmol), triethylamine (63.0 mg, 0.6 mmol), DMAP (2.0 mg, 0.02 mmol), mixed in dichloromethane (9.0 mL), reacted at room temperature for 30 min, the reaction solution was separated with dichloromethane (50.0 mL) and water (20.0 mL), and separated. The organic phase was washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound (R)-5-chloro-N-(2-((2-methoxyl -3-Nitropyridin-5-yl)methoxy)propyl)-N-Boc-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e ]pyrimidine-3-carboxamide (120.0 mg, 71.4% yield).

MS m/z(ESI): 562.1,564.1[M+H] ⁺ .

The seventh step: (R)-5-chloro-N-(2-((2-methoxy-3-aminopyridin-5-yl)methoxy)propyl)-N-Boc-7,8- Preparation of Dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

(R)-5-Chloro-N-(2-((2-methoxy-3-nitropyridin-5-yl)methoxy)propyl)-N-Boc-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (37.7mg, 0.07mmol), iron powder (18.8mg, 0.3mmol), ammonium chloride (18.0 mg, 0.3 mmol), water (0.6 mL), mixed in ethanol (3.0 mL), reacted at 65°C for 1 h, cooled to room temperature, filtered under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was washed with ethyl acetate (20.0 mL). ) and water (10.0 mL) were separated, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and purified by prep-TLC to obtain compound (R)-5-chloro-N-(2- ((2-Methoxy-3-aminopyridin-5-yl)methoxy)propyl)-N-Boc-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo [3,2-e]pyrimidine-3-carboxamide (19.0 mg, 51.4% yield).

MS m/z(ESI): 532.2,534.2[M+H] ⁺ .

The eighth step: (R, 1 ³ E, 1 ⁴ E)-3 ² -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8- Diaza-N-Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(3,5)-benzocyclononyl-9 - Preparation of ketones

(R)-5-Chloro-N-(2-((2-methoxy-3-aminopyridin-5-yl)methoxy)propyl)-N-Boc-7,8-dihydro-6H - Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (95.0 mg, 0.2 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2', 4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (29.0 mg, 0.04 mmol), Cesium carbonate (119.0 mg, 0.4 mmol) was mixed in 1,4-dioxane (10.0 mL), the reaction system was replaced with nitrogen three times, reacted at 82 °C for 5 h, cooled to room temperature, concentrated under reduced pressure, and obtained after column chromatography Compound ( ^R ,13E,14E)-32 ^- methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2,8-diaza -N-Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(3,5)-benzocyclononyl-9-one ( 55.0 mg, the yield is 55.6%).

MS m/z(ESI): 496.2[M+H] ⁺ .

The ninth step: ( ^R ,13E,14E)-32-methoxy- ⁷ -methyl- ^17,18 -dihydro-16H- ⁵ -oxa ^- ^2,8- Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(3,5)-benzocyclononyl-9-one (Ia -7) Preparation

( ^R ,13E,14E)-32 ^- methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2,8-diaza- N-Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(3,5)-benzocyclononyl-9-one (9.0 mg, 0.02 mmol), ethanolic hydrochloric acid solution (15.0%) (3.0 mL), ethyl acetate (1.0 mL), added to a 25 mL round-bottom flask, reacted at room temperature for 5 h, and adjusted pH with saturated aqueous sodium bicarbonate solution at 0 °C = 8.0, the residue was separated with ethyl acetate (50.0 mL) and water (30.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by a preparative plate. Compound ( ^R ,13E,14E)-32 ^- methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2,8-diaza -1(5,3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(3,5)-benzocyclononyl-9-one (Ia-7) (3.0 mg, 38.0% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.34(d, 2H), 8.24(d, 1H), 8.10(s, 1H), 6.88(d, 1H), 6.65(d, 1H), 4.58( d, 1H), 4.32(d, 1H), 3.89(s, 3H), 3.71(t, 3H), 3.65(dd, 1H), 3.21-3.09(m, 3H), 1.14(d, 3H).

MS m/z(ESI): 396.2[M+H] ⁺ .

Example 10, (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3 )-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ib-6) preparation

^The first step: ( ^R ,13E,14E)-35-methoxy- ⁷ -methyl-18H- ⁵ -oxa-2,8-diaza-1(5,3 )-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one

( ^R ,13E,14E)-35-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- ^16H - ⁵ -oxa-2,8-diaza- 1(5,3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (5.0 mg, 0.01 mmol ), manganese dioxide (109.8 mg, 1.26 mmol), dichloromethane (5.0 mL), dimethyl sulfoxide (0.5 mL), were added to a 25 mL round-bottom flask, reacted at room temperature for 6 h, filtered, and the filtrate was concentrated under reduced pressure to prepare Compound ( ^R ,13E,14E)-35-methoxy- ⁷ -methyl- ^18H - ⁵ -oxa-2,8-diaza-1(5,3 )-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ib-6) (2.0 mg, yield 40.2%).

¹ H NMR (400MHz, DMSO-d ₆ )δ: 13.22-13.01(m, 1H), 8.90(s, 1H), 8.33(d, 2H), 8.23(d, 1H), 8.15(s, 1H), 6.83(d,1H),6.65(d,1H),4.58(d,1H),4.32(d,1H),3.90(s,3H),4.00-3.80(m,1H),3.65(dd,1H) ,3.24-3.01(m,1H),1.14(d,3H).

MS m/z(ESI): 394.1[M+H] ⁺ .

Example 11, (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -methoxy-7-methyl-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxa-2,8- Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ia -5) Preparation

The first step: the preparation of 5-bromomethyl-3-methoxybromobenzene

3-Methoxy-5-methyl-5 bromobenzene (5.0 g, 24.9 mmol), N-bromosuccinimide (4.9 g, 27.4 mmol), azobisisobutylcyanide (0.4 g, 2.5 mmol), mixed in carbon tetrachloride (50.0 mL), reacted at 80° C. for 5 h, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the compound 5-bromomethyl-3-methoxybromobenzene was obtained by column chromatography ( 5.2g, the yield is 74.6%).

The second step: preparation of (R)-2-(N-Boc-amino)propyl-(3-bromo-5-methoxybenzyl)ether

5-Bromomethyl-3-methoxybromobenzene (2.0g, 7.1mmol), (D)-N-Boc-propanamine (1.5g, 8.6mmol), sodium hydride (content 60%) (1.0g, 17.2 mmol), mixed in N,N-dimethylformamide (30.0 mL), reacted at room temperature for 4 h, the reaction solution was added with ethyl acetate (100.0 mL), water (50.0 mL), separated, the organic phase was separated and saturated with Wash with aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound (R)-2-(N-Boc-amino)propyl-(3-bromo-5-methoxy) by column chromatography benzyl) ether (1.9 g, 97.9% yield).

MS m/z(ESI): 274.2,276.2[M+H-100] ⁺ .

The third step: preparation of (R)-2-(N-Boc-amino)propyl-(3-(N-Boc-amino)-5-methoxybenzyl)ether

(R)-2-(N-Boc-amino)propyl-(3-bromo-5-methoxybenzyl)ether (0.7 g, 1.9 mmol), 1,1'-binaphthyl-2,2' - bisdiphenylphosphine (0.7 g, 1.1 mmol), dipalladium tridibenzylideneacetone (0.5 g, 0.6 mmol), cesium carbonate (3.6 g, 11.0 mmol), 1,4-dioxane (18.0 mL) ), mixed in a 50mL single-neck flask, reacted at 110°C for 20h, filtered, the filtrate was concentrated under reduced pressure, and the compound (R)-2-(N-Boc-amino)propyl-(3-(N-) was obtained after silica gel column chromatography Boc-amino)-5-methoxybenzyl) ether (1.0 g, 100% yield).

MS m/z(ESI): 311.2[M+H-100] ⁺ .

The fourth step: the preparation of (R)-2-aminopropyl-(3-amino-5-methoxybenzyl) ether

(R)-2-(N-Boc-amino)propyl-(3-(N-Boc-amino)-5-methoxybenzyl)ether (0.7 g, 1.6 mmol), dichloromethane (10.0 mL) ), trifluoroacetic acid (3.5mL), mixed in a 50mL single-neck flask, reacted at room temperature for 2h, concentrated under reduced pressure, added ethyl acetate (50.0mL), water (50.0mL) to the residue, separated, discarded the organic phase, The aqueous phase was adjusted to pH=9 with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane/methanol=10/1 (v/v), the organic phase was separated and washed with saturated aqueous sodium chloride solution, and the organic phase was washed with anhydrous sodium sulfate After drying and concentration under reduced pressure, compound (R)-2-aminopropyl-(3-amino-5-methoxybenzyl) ether (0.3 g, yield 89.3%) was obtained.

MS m/z(ESI): 211.1[M+H] ⁺ .

The fifth step: (R)-5-chloro-N-(2-(((5-methoxy-3-amino)benzyloxy)propyl)-N-Boc-6,7-dihydro-8H - Preparation of pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

N-Boc-5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (300.0 mg, 1.3 mmol), ( R)-2-aminopropyl-(3-amino-5-methoxybenzyl) ether (230.0 mg, 0.9 mmol), 2-(7-azabenzotriazole)-N,N,N ',N'-Tetramethylurea hexafluorophosphate (0.1 g, 0.3 mmol), triethylamine (57.0 mg, 0.6 mmol) were mixed in dichloromethane (14.0 mL), and the reaction was stirred at 25 °C for 16 h under reduced pressure. Concentration, column chromatography to obtain compound (R)-5-chloro-N-(2-(((5-methoxy-3-amino)benzyloxy)propyl)-N-Boc-6,7-di Hydrogen-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (100.0 mg, 14.5% yield).

MS m/z(ESI): 531.1,533.1[M+H] ⁺ .

The sixth step: ( ^R ,13E,14E) ^-35 -methoxy- ⁷ -methyl- ^17,18 -dihydro-16H- ⁵ -oxa ^- 2,8- Diaza-N-Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9 - Preparation of ketones

(R)-5-Chloro-N-(2-(((5-methoxy-3-amino)benzyloxy)propyl)-N-Boc-6,7-dihydro-8H-pyrazolo [1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (90.0 mg, 0.2 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6 '-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13.0 mg, 0.02 mmol), cesium carbonate (110.0 mg, 0.3 mmol), mixed in 1,4-dioxane (9.0 mL), the reaction system was replaced with nitrogen three times, reacted at 82°C for 5 h, cooled to room temperature, concentrated under reduced pressure, and obtained compound (R, 13E,14E)-35 ^- methoxy- ⁷ -methyl- ^17,18 -dihydro-16H ^- ⁵ -oxa-2,8-diaza ^- N-Boc -1(5,3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (45.0 mg, received rate was 45.5%).

MS m/z(ESI): 495.2[M+H] ⁺ .

The seventh step: ( ^R ,13E,14E) ^-35 -methoxy- ⁷ -methyl- ^17,18 -dihydro-16H- ⁵ -oxa ^- 2,8- Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ia -5) Preparation

( ^R ,13E,14E)-35-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- ^16H - ⁵ -oxa-2,8-diaza- N-Boc-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (40.0 mg, 0.08 mmol), ethanolic hydrochloric acid solution (15.0%) (2.0 mL), ethyl acetate (2.0 mL), added to a 25 mL round-bottom flask, reacted at room temperature for 5 h, and adjusted pH with saturated aqueous sodium bicarbonate solution at 0 °C = 8, the residue was separated with ethyl acetate (50.0 mL) and water (30.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative plate. Compound ( ^R ,13E,14E)-35-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- ^16H - ⁵ -oxa-2,8-diaza -1(5,3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ia-5) (30.0 mg, yield 93.8%).

¹ H NMR (400MHz, DMSO-d ₆ )δ: 9.09(s,1H), 8.34(d,2H), 8.23(d,1H), 8.16(s,1H), 6.91(d,1H), 6.75( d,1H),4.62(d,1H),4.40(d,1H),4.11-3.83(m,3H),3.70(s,3H),3.50(dd,1H),3.21-3.09(m,3H) ,1.10(d,3H).

MS m/z(ESI): 395.1[M+H] ⁺ .

Example ¹² , ( ^R ,13E,14E)-35-methoxy- ⁷ -methyl-18H- ⁵ -oxa-2,8-diaza-1(5,3 )-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ib-2) preparation

The eighth step: (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -methoxy-7-methyl-1 ⁸ H-5-oxa-2,8-diaza-1(5,3 )-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ib-2) preparation

( ^R ,13E,14E)-35-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- ^16H - ⁵ -oxa-2,8-diaza- 1(5,3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (15.0 mg, 0.04 mmol ), manganese dioxide (272mg, 3.12mmol), dichloromethane (8.0mL), dimethyl sulfoxide (1.0mL), added to a 25mL round bottom flask, reacted at room temperature for 6h, filtered, and the filtrate was concentrated under reduced pressure to prepare a plate Compound ( ^R ,13E,14E)-35-methoxy- ⁷ -methyl- ^18H - ⁵ -oxa-2,8-diaza-1(5,3) was isolated -Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononyl-9-one (Ib-2) (4.0 mg, the yield is 25.4%).

¹ H NMR (400MHz, DMSO-d ₆ )δ: 13.01-12.87(m, 1H), 9.07(s, 1H), 8.44(s, 1H), 8.31(d, 2H), 8.21(d, 1H), 8.12(s, 1H), 6.96(d, 1H), 6.77(d, 1H), 4.62(d, 1H), 4.41(d, 1H), 4.00-3.89(m, 1H), 3.70(s, 3H) ,3.50(dd,1H),3.21-3.15(m,1H),1.10(d,3H).

MS m/z(ESI): 393.1[M+H] ⁺ .

Example ¹³ , ( ^R ,13E,14E)-34 ^- fluoro-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa -2,8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclocyclononyl- Preparation of 9-ketone (Ia-2)

The first step: the preparation of 2-fluoro-4-methoxy-5-nitrobenzaldehyde

2-Fluoro-4-methoxybenzaldehyde (2.0g, 13.0mmol) was dissolved in concentrated sulfuric acid (1.6mL), the ice brine was cooled to -12°C, and concentrated sulfuric acid (1.6mL) was added dropwise to concentrated nitric acid ( 1.6mL), then add the mixed acid dropwise to the reaction system, control the temperature not to exceed 0 ° C, react for 2h, pour the reaction solution into ice water, stir for 15 minutes, filter, filter cake column chromatography to obtain a pale yellow solid compound 2-Fluoro-4-methoxy-5-nitrobenzaldehyde (1.6 g, 61.8%).

MS m/z(ESI): 200[M+H] ⁺ .

The second step: preparation of 2-fluoro-4-methoxy-5-nitrobenzyl alcohol

2-Fluoro-4-methoxy-5-nitrobenzaldehyde (0.5g, 2.5mmol) was dissolved in methanol (7.0mL), the ice water was cooled to 0°C, and sodium borohydride (0.2g, 2.5 mmol) was added in batches. 5mmol), react at 0°C for 1 h, pour the reaction solution into water, extract twice with dichloromethane, combine the dichloromethane, wash with saturated brine, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain 2-Fluoro-4-methoxy-5-nitrobenzyl alcohol (0.5 g, 98.0%).

MS m/z(ESI): 202.1[M+H] ⁺ .

The third step: preparation of 2-fluoro-4-methoxy-5-nitrobenzyl bromide

2-Fluoro-4-methoxy-5-nitrobenzyl alcohol (0.3 g, 1.5 mmol), triphenylphosphine (0.8 g, 3.0 mmol) were dissolved in tetrahydrofuran (5.0 mL), carbon tetrabromide (1.0 g, 3.0 mmol) was dissolved in tetrahydrofuran (2.0 mL) and added dropwise to the reaction system, stirred at room temperature overnight, concentrated under reduced pressure and column chromatography to obtain a pale yellow solid compound 2-fluoro-4-methoxy-5-nitro Benzyl bromide (0.3 g, 80.3%).

MS m/z(ESI): 264.2[M+H] ⁺ .

The fourth step: preparation of (R)-(1-((2-fluoro-4-methoxy-5-nitrobenzyl)oxy)prop-2-yl)carbamic acid tert-butyl ester

(R)-(1-hydroxypropan-2-yl) tert-butyl carbamate (0.3 g, 1.8 mmol) was dissolved in tetrahydrofuran (7.0 mL), cooled to 0 °C with ice water, sodium hydride (72.0 mg, 1.8 mmol), stirred under ice water for 30 minutes, added 2-fluoro-4-methoxy-5-nitrobenzyl bromide (0.5 g, 1.7 mmol), stirred at room temperature overnight, poured the reaction solution into water, added ethyl acetate Ester extraction twice, combined with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and column chromatography to obtain pale yellow solid compound (R)-(1-((2-Fluoro-4-methoxy-5-nitro tert-butyl benzyl)oxy)prop-2-yl)carbamate (0.26 g, 41.9%).

MS m/z(ESI): 359.2[M+H] ⁺ .

The fifth step: preparation of (R)-(1-((5-amino-2-fluoro-4-methoxybenzyl)oxy)prop-2-yl)carbamic acid tert-butyl ester

(R)-(1-((2-Fluoro-4-methoxy-5-nitrobenzyl)oxy)prop-2-yl)carbamate tert-butyl ester (0.1 mg, 0.3 mmol) in methanol (4.0mL), then add Raney nickel (0.4g), ventilate with hydrogen balloon, stir at room temperature for one hour, filter and concentrate to dryness to obtain a colorless oily compound, add saturated sodium bicarbonate solution to adjust pH=10.0, stir for 10 minutes , extracted twice with dichloromethane, concentrated under reduced pressure, and column chromatography gave a pale yellow oily compound (R)-(1-((5-amino-2-fluoro-4-methoxybenzyl)oxy)propane -2-yl) tert-butyl carbamate (0.1 g, 98.3%).

MS m/z(ESI): 329.2[M+H] ⁺ .

The sixth step: the preparation of (R)-5-((2-aminopropoxy) methyl)-4-fluoro-2-methoxyaniline hydrochloride

(R)-(1-((5-Amino-2-fluoro-4-methoxybenzyl)oxy)prop-2-yl)carbamate tert-butyl ester (0.1 g, 0.3 mmol) was dissolved in dihydrochloride in oxane (5.0 mL), stirred at 50°C for 20 minutes, and concentrated to give crude product (R)-5-((2-aminopropoxy)methyl)-4-fluoro-2-methoxyaniline hydrochloride Salt (0.09 g, 100.0%).

MS m/z(ESI): 229.2[M+H] ⁺ .

The seventh step: (R)-N-(1-((5-amino-2-fluoro-4-methoxybenzyl)oxy)propan-2-yl)-5-chloro-8-((2 -(Trimethylsilyl)ethoxy)methyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-3-carboxamide preparation

(R)-5-((2-Aminopropoxy)methyl)-4-fluoro-2-methoxyaniline hydrochloride (90.0 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (3 mL), was added triethylamine (109.0 mg, 1.1 mmol), and then 5-chloro-8-((2-(trimethylsilyl)ethoxy)methyl)-7,8-di Hydrogen-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (114.0 mg, 0.3 mmol), N,N,N',N'-tetramethyl -O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (141.0 mg, 0.4 mmol), triethylamine (109.0 mg, 1.1 mmol), N,N-dimethylformamide ( 3mL) mixed solution was added, stirred at room temperature for two hours, added water and ethyl acetate for extraction 3 times, combined the organic phases, washed with saturated brine, concentrated under reduced pressure and column chromatography to obtain a colorless solid compound (R)-N- (1-((5-Amino-2-fluoro-4-methoxybenzyl)oxy)propan-2-yl)-5-chloro-8-((2-(trimethylsilyl)ethyl) oxy)methyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-3-carboxamide (124.0 mg, 71.7%).

MS m/z(ESI): 579.1[M+H] ⁺ .

The eighth step: (R, 1 ³ E, 1 ⁴ E)-3 ⁴ -fluoro-3 ⁶ -methoxy-7-methyl-1 ⁸ -((2-(trimethylsilyl)ethoxy yl)methyl) ^-17,18 -dihydro-16H ^- ⁵ -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrole Preparation of [3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one

(R)-N-(1-((5-Amino-2-fluoro-4-methoxybenzyl)oxy)propan-2-yl)-5-chloro-8-(((2-(trimethyl) silyl)ethoxy)methyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-3-carboxamide (69.0 mg, 0.1 mmol) was dissolved in dioxane (3.5 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) was added ) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (38.0 mg, 0.05 mmol), cesium carbonate (78.0 mg, 0.24 mmol), stirred at 90°C for 3.0 hours, cooled to room temperature , added a small amount of methanol, filtered, concentrated, and separated by preparative plate to obtain a white solid ( ^R ,13E, ^14E )-34 ^- fluoro-36-methoxy- ⁷ -methyl- ¹⁸ -((2 -(Trimethylsilyl)ethoxy)methyl) ^-17,18 -dihydro-16H ^- ⁵ -oxa-2,8-diaza-1(5,3)- Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (39.0 mg, 60.0%).

MS m/z(ESI): 543.1[M+H] ⁺ .

^The ninth step: ( ^R ,13E,14E)-34 ^- fluoro-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa -2,8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclocyclononyl- Preparation of 9-keto (Ia-2)

( ^R ,13E, ^14E )-34 ^- Fluoro ^- 36-methoxy-7-methyl- ¹⁸ -((2-(trimethylsilyl)ethoxy)methyl ) ^-17,18 -dihydro-16H ^- ⁵ -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3, 2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (24.0 mg, 0.04 mmol) was dissolved in trifluoroacetic acid (2.0 mL), stirred at 50°C for 20 minutes, cooled to room temperature, added A small amount of water and methanol were adjusted to pH=8.0 with saturated aqueous sodium bicarbonate solution, stirred for 5 minutes, extracted twice with dichloromethane, the organic phase was washed with saturated brine, separated, the organic phase was concentrated to dryness, and the preparation plate was separated to obtain a white Solid ( ^R ,13E, ^14E )-34 ^- fluoro-36-methoxy- ⁷ -methyl- ^17,18 -dihydro ^- 16H- ⁵ -oxa-2, 8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclocyclononyl-9-one (Ia-2) (8.0 mg, 44.4%).

MS m/z(ESI): 413.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.38(s,1H), 8.1(s,1H), 7.35(s,1H), 7.12(s,1H), 6.52(s,1H), 6.22( s,1H),4.63(d,2H),3.90-3.92(m,1H),3.86(s,3H),3.57(d,2H),3.55(d,2H),3.01(d,2H),1.26 (d,3H).

Example 14, (R, 1 ³ E, 1 ⁴ E)-3 ⁴ -fluoro-3 ⁶ -methoxy-7-methyl-1 ^8hydro -5-oxa-2,8-diaza- 1(5,3)-Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one (Ib-5) preparation

( ^R ,13E,14E)-34 ^- Fluoro ^- ³⁶ -methoxy- ⁷ -methyl-17,18-dihydro ^- 16H- ⁵ -oxa-2,8 - Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclononyl-9-one ( 15mg, 0.036mmol), dissolved in dichloromethane (20mL), added manganese dioxide (31mg, 0.36mmol), stirred at room temperature for 2h, added a small amount of dichloromethane and filtered, scraping a large plate to obtain a white solid compound (R, ^1.3 E,14E)-34-Fluoro- ³⁶ -methoxy- ⁷ -methyl- ^18hydro - ⁵ -oxa-2,8-diaza-1(5,3)-pyrazole Lo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclocyclononyl-9-one (Ib-5) (8 mg, 54.4%).

MS m/z(ESI): 411[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.20(s,1H), 8.38(s,1H), 8.15(s,1H), 7.92(s,1H), 7.35(s,1H), 7.12 (s,1H),6.55(s,1H),6.22(s,1H),4.63-4.58(m,2H),3.90-3.85(m,1H),3.86(s,3H),3.55(d,2H) ),1.26(d,3H).

Example 15, (R, 1 ³ E, 1 ⁴ E)-7-methyl-3 ⁶ -(2-oxopyrrolidin-1-yl)-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5 -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridinecyclononane Synthesis of Alk-9-one (Ia-4)

The first step: the synthesis of 2-chloro-6-(2-oxypyrrolidin-1-yl) isonicotinic acid methyl ester

Methyl 2,6-dichloroisonicotinate (5.0 g, 24.5 mmol), 2-pyrrolidone (0.4 g, 24.5 mmol), tris(dibenzylidene-BASE acetone)dipalladium (2.3 g, 2.5 mmol), 2 -(Dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (2.0 g, 3.7 mmol), mixed in 1, 4-dioxane (100.0 mL) was reacted in an oil bath at 90°C for 20.0 h, the reaction solution was cooled, concentrated, and directly passed through the column to obtain 2-chloro-6-(2-oxopyrrolidin-1-yl) Methyl isonicotinate (3.3 g, 53% yield).

MS m/z (ESI): 254.1 [M+H] ⁺ .

The second step: synthesis of 1-(6-chloro-4-(hydroxymethyl)pyridin-2-yl)pyrrolidin-2-one

Methyl 2-chloro-6-(2-oxopyrrolidin-1-yl)isonicotinate (3.3 g, 13.0 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), and anhydrous lithium chloride (818.0 mg, 19.5mmol), in an ice-water bath at 0°C, sodium borohydride (593.0mg, 15.6mmol) was added in batches, after the addition was completed, the ice-water bath was removed, the temperature was naturally raised, and the reaction was performed at room temperature for 12.0h. 50.0 mL of water was added to the system, extracted with ethyl acetate (200.0 mL*3), dried, and passed through the column to obtain 1-(6-chloro-4-(hydroxymethyl)pyridin-2-yl)pyrrolidine -2-one (2.0 g, 69% yield).

MS m/z (ESI): 226.1 [M+H] ⁺ .

The third step: synthesis of 1-(4-(bromomethyl)-6-chloropyridin-2-yl)pyrrolidin-2-one

1-(6-Chloro-4-(hydroxymethyl)pyridin-2-yl)pyrrolidin-2-one (2.0 g, 9.0 mmol) was dissolved in dichloromethane (20.0 mL) and triphenylphosphine was added (3.5g, 13.5mmol), carbon tetrabromide (4.4g, 13.5mmol), react at room temperature for 2h, after TLC monitoring that the reaction of the raw materials is basically complete, directly spin dry, and pass through the column to obtain 1-(4-(bromomethyl) -6-Chloropyridin-2-yl)pyrrolidin-2-one (2.0 g, 77% yield).

MS m/z (ESI): 288.1 [M+H] ⁺ .

The fourth step: tert-butyl (R)-(1-((2-chloro-6-(2-oxypyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl)amino Synthesis of Formate

1-(4-(Bromomethyl)-6-chloropyridin-2-yl)pyrrolidin-2-one (2.0 g, 7.0 mmol), N-Boc-D alaninol (2.0 g, 8.0 mmol), Sodium hydride (content 60%) (0.5 g, 11.0 mmol) was mixed in N,N-dimethylformamide (25.0 mL), reacted at room temperature for 4.0 h, 150.0 mL of ethyl acetate and 50.0 mL of water were added to the reaction solution, Separation, separating the organic phase and washing with saturated aqueous sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure, column chromatography to obtain tert-butyl (R)-(1-((2-chloro-6-( 2-Oxypyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl)carbamate (1.2 g, 46% yield).

MS m/z (ESI): 327.1 [M+H-56] ⁺ .

The fifth step: tert-butyl (R)-(1-((2-((tert-butoxycarbonyl)amino)-6-(2-oxypyrrolidin-1-yl)pyridin-4-yl)methoxy ) Synthesis of propan-2-yl)carbamate

tert-Butyl (R)-(1-((2-Chloro-6-(2-oxopyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl)carbamate ( 1.2g, 3.1mmol), tert-butyl carbamate (550.0mg, 4.5mmol), tris(dibenzylidene-BASE acetone)dipalladium (275.0mg, 0.3mmol), 2-(dicyclohexylphosphine)-3, 6-Dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (268.0 mg, 0.5 mmol) mixed in 1,4-dioxane (100.0 mL) in an oil bath at 90 °C for 20.0 h, the reaction solution was cooled, concentrated, and passed through a column to obtain tert-butyl(R)-(1-((2-((tert-butoxycarbonyl)amino)-6-(2 -Oxypyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl)carbamate (0.6 g, 43% yield).

MS m/z (ESI): 408.1 [M+H-56] ⁺ .

The sixth step: synthesis of (R)-1-(6-amino-4-((2-aminopropoxy)methyl)pyridin-2-yl)pyrrolidin-2-one

tert-Butyl(R)-(1-((2-((tert-butoxycarbonyl)amino)-6-(2-oxopyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2 -yl) carbamate (450.0 mg, 1.0 mmol), dichloromethane (10.0 mL), trifluoroacetic acid (5.0 mL), mixed in a 50 mL single-necked flask, reacted at room temperature for 2.0 h, concentrated under reduced pressure, and the residue was added Ethyl acetate (100.0 mL), water (50.0 mL), separated, the aqueous phase was adjusted to pH=9 with saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane/methanol=10/1 (v/v), separated The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-1-(6-amino-4-((2-aminopropoxy)methyl)pyridine -2-yl)pyrrolidin-2-one (130.0 mg, 51% yield).

MS m/z(ESI): 264.2[M+H] ⁺ .

The seventh step: tert-butyl (R)-N-(1-((2-amino-6-(2-oxypyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl )-5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-N-Boc-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (83.0 mg, 0.3 mmol), (R)-1-(6-Amino-4-((2-aminopropoxy)methyl)pyridin-2-yl)pyrrolidin-2-one (130.0 mg, 0.5 mmol), N,N,N ',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (190.0 mg, 0.5 mmol), triethylamine (76.0 mg, 0.8 mmol) were mixed in two In chloromethane (5.0 mL), the reaction was stirred at room temperature for 2.0 h. After monitoring the completion of the reaction by TLC, it was concentrated under reduced pressure, and tert-butyl (R)-N-(1-(((2-amino-6-(2) was obtained by column chromatography. -Oxypyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl)-5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrole and [3,2-e]pyrimidine-3-carboxamide (80.0 mg, 55% yield).

MS m/z(ESI): 584.2,586.2[M+H] ⁺ .

The eighth step: tert-butyl (R, 1 ³ E, 1 ⁴ E)-7-methyl-9-oxo-3 ⁶ -(2-oxopyrrolidin-1-yl)-1 ⁷ ,1 ⁸ - Dihydro-1 ⁶ H-5-oxo-2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2 Synthesis of ,4)-pyridinecyclononane-1 ⁸ -carboxylic acid amine

tert-Butyl(R)-N-(1-((2-Amino-6-(2-oxopyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl)-5- Chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (80.0 mg, 0.14 mmol), methanesulfonic acid (2- Di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium ( II) (10.0mg, 0.02mmol), cesium carbonate (86.0mg, 0.26mmol), mixed in 1,4-dioxane (14.0mL), the reaction system was replaced with nitrogen three times, reacted at 80°C overnight, cooled to room temperature , concentrated under reduced pressure, and column chromatography gave tert ^- butyl( ^R ,13E,14E)-7-methyl-9-oxo-36-(2-oxopyrrolidin-1-yl)-17 ,18-Dihydro-16H-5-oxo-2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3( 2,4)-Pyridinecyclononane- ¹⁸ -carboxylic acid amine (38.0 mg, 51% yield).

MS m/z(ESI): 548.2[M+H] ⁺ .

The ninth step: (R, 1 ³ E, 1 ⁴ E)-7-methyl-3 ⁶ -(2-oxopyrrolidin-1-yl)-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5 -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridinecyclononane Synthesis of Alk-9-one (Ia-4)

tert-Butyl( ^R ,13E,14E)-7-methyl- ⁹ -oxo-36-(2-oxopyrrolidin- ¹ ^- yl) ^-17,18 -dihydro-16H -5-oxo-2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridine ring Nonane- ¹⁸ -carboxylic acid amine (38.0mg, 0.07mmol), hydrochloric acid dioxane solution (4.0M) (4.0mL), added to 25mL single-neck flask, reacted at room temperature for 2h, at 0 ℃ with saturated carbonic acid Aqueous sodium hydrogen solution was adjusted to pH=8.0, the residue was separated with ethyl acetate (30.0 mL) and water (10.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure (R, 1 ³ E, 1 ⁴ E)-7-methyl-3 ⁶ -(2-oxopyrrolidin-1-yl)-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5 was prepared by post-HPLC - Oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridinecyclononane Alkan-9-one (Ia-4) (20.0 mg, 64% yield).

MS m/z(ESI): 448.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.44(s,1H), 8.25(d,1H), 8.14(s,1H), 8.07(d,1H), 7.78(s,1H), 7.38( d,1H),4.32(dd,2H),4.12(m,2H),3.94(dd,1H),3.85(t,2H),3.48(d,1H),3.41(dd,1H),3.24–3.09 (m, 2H), 2.24–2.09 (m, 4H), 1.13 (d, 3H).

Example 16, (R, 1 ³ E, 1 ⁴ E)-7-methyl-3 ⁶ -(2-oxopyrrolidin-1-yl)-1 ⁸ H-5-oxa-2,8-heavy Nitrogen-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-3(2,4)-pyridinecyclononan-9-one (Ib-8) preparation

The first step: (R, 1 ³ E, 1 ⁴ E)-7-methyl-3 ⁶ -(2-oxopyrrolidin-1-yl)-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5 -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridinecyclononane Alkan-9-one (10 mg, 0.02 mmol) was added with dichloromethane (4 mL) and 2 drops of dimethyl sulfoxide. After the solution was clarified, manganese dioxide (2.0 mg, 4.0 mmol) was added and reacted at room temperature for 2 h. After monitoring the completion of the reaction by TLC, the filtrate was filtered, and the filtrate was directly prepared by HPLC to obtain (R, 1 ³ E, 1 ⁴ E)-7-methyl-3 ⁶ -(2-oxopyrrolidin-1-yl)-1 ⁸ H-5 -oxa-2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridinecyclononane -9-keto (Ib-8) (6.0 mg, 66%).

MS m/z(ESI): 446.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(s,1H), 8.27(d,1H), 8.17(s,1H), 8.09(d,1H), 7.90(s,1H), 7.48( d, 1H), 4.31(m, 2H), 4.12(m, 2H), 3.74(dd, 1H), 3.48(d, 1H), 3.41(dd, 1H), 3.24–3.09(m, 2H), 2.24 –2.09(m, 2H), 1.13(d, 3H).

Example 17, (R, 1 ³ E, 1 ⁴ E)-7-methyl-9-oxo-1 ⁷ ,1 ⁸ -dihydro-16H-5-oxo-2,8-diazo-1 (Ia-3) of (5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane-35-carbonitrile preparation

The first step: the synthesis of 5-bromomethyl-3-bromo-benzonitrile

3-Bromo-5-methylbenzonitrile (5.0 g, 25.0 mmol), N-bromosuccinimide (5.3 g, 30.0 mmol), azobisisobutyl cyanide (0.5 g, 3 mmol), mixed in In carbon tetrachloride (50.0 mL), the reaction was carried out at 80 °C for 8.0 h, cooled to room temperature, concentrated under reduced pressure, and subjected to column chromatography to obtain the compound 5-bromomethyl-3-bromo-benzonitrile (4.6 g, the yield was 67%). ).

The second step: (R)-2-(N-Boc-amino)propyl-(5-bromo-3-cyanobenzyl)ether

4-Bromomethyl-3-bromo-benzonitrile (2.0g, 7.3mmol), N-Boc-D alaninol (2.0g, 8.0mmol), sodium hydride (content 60%) (0.5g, 11.0mmol) , mixed in N,N-dimethylformamide (25.0 mL), reacted at room temperature for 4.0 h, added 150.0 mL of ethyl acetate and 50.0 mL of water to the reaction solution, separated, separated the organic phase and washed with saturated aqueous sodium chloride solution, The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the compound 2-(N-Boc-amino)propyl-(5-bromo-3-cyanobenzyl)ether (1.1 g, the yield was 41%).

MS m/z (ESI): 313 [M+H-56] ⁺ .

The third step: Synthesis of 2-(N-Boc-amino)propyl-(5-N-Boc-amino-3-cyanobenzyl)ether

(R)-2-(N-Boc-amino)propyl-(5-bromo-3-cyanobenzyl)ether (800.0 mg, 2.2 mmol), tert-butyl carbamate (381.0 mg, 3.3 mmol), Tris(dibenzylidene-BASE acetone)dipalladium (183.0 mg, 0.2 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I- Propyl-11'-biphenyl (161.0 mg, 0.3 mmol), mixed in 1,4-dioxane (20.0 mL), reacted in an oil bath at 90 °C for 20.0 h, the reaction solution was cooled, concentrated, and passed through column , to obtain the target compound (R)-2-(N-Boc-amino)propyl-(5-N-Boc-amino-3-cyanobenzyl)ether (460.0 mg, yield 51%).

MS m/z (ESI): 350.2 [M+H-56] ⁺ .

The fourth step: the synthesis of (R)-2-aminopropyl-(5-amino-3-cyanobenzyl) ether

(R)-2-(N-Boc-amino)propyl-(5-N-Boc-amino-3-cyanobenzyl)ether (460.0 mg, 1.1 mmol), dichloromethane (10.0 mL), trichloromethane Fluoroacetic acid (5.0 mL) was mixed in a 50 mL single-necked flask, reacted at room temperature for 2.0 h, concentrated under reduced pressure, added ethyl acetate (100.0 mL) and water (50.0 mL) to the residue, and separated the aqueous phase with saturated sodium bicarbonate. The aqueous solution was adjusted to pH=9.0, the aqueous phase was extracted with dichloromethane/methanol=10/1 (v/v), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound (R)-2-aminopropyl-(5-amino-3-cyanobenzyl) ether (150.0 mg, 66% yield).

MS m/z(ESI): 206.2[M+H] ⁺ .

The fifth step: (R)-5-chloro-N-(1-(((5-amino-3-cyanobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H- Synthesis of Pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide

5-Chloro-N-Boc-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (75.0 mg, 0.2 mmol), (R)-2-Aminopropyl-(5-amino-3-cyanobenzyl) ether (87.0 mg, 0.4 mmol), N,N,N′,N′-tetramethyl-O-(7- Azabenzotriazol-1-yl) urea hexafluorophosphate (167.0 mg, 0.4 mmol), triethylamine (67.0 mg, 0.7 mmol) were mixed in dichloromethane (5.0 mL), and the reaction was stirred at room temperature for 2.0 h, After monitoring the completion of the reaction by TLC, concentration under reduced pressure and column chromatography to obtain compound (R)-5-chloro-N-(1-(((5-amino-3-cyanobenzyl)oxy)propan-2-yl )-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (72.0 mg, 65% yield).

MS m/z(ESI): 526.2,528.2[M+H] ⁺ .

The sixth step: tert-butyl (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -cyano-7-methyl-9-oxo-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5- Oxo-2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane Synthesis of -1 ⁸ -Carboxylic acid amine

(R)-5-Chloro-N-(1-(((5-amino-3-cyanobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H-pyrazolo[ 1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide (72.0 mg, 0.14 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0mg, 0.02mmol), cesium carbonate (88.0mg , 0.3 mmol), mixed in 1,4-dioxane (15.0 mL), the reaction system was replaced with nitrogen three times, reacted at 80° C. overnight, cooled to room temperature, concentrated under reduced pressure, and the compound tert-butyl was obtained after column chromatography ( ^R ,13E,14E)-35 ^- cyano- ⁷ -methyl- ⁹ -oxo-17,18-dihydro ^- 16H- ⁵ -oxo-2,8-heavy Nitrogen-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane- ¹⁸ -carboxylic acid amine Synthesis (28.0 mg, 41% yield).

MS m/z(ESI): 488.2[M+H] ⁺ .

The seventh step: ( ^R ,13E,14E)-35 ^- cyano- ⁷ -methyl- ⁹ -oxo- ^17,18 -dihydro-16H- ⁵ -oxo- 2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane-1 ⁸ -Synthesis of Carboxylic Acid Amines (Ia-3)

tert ^- Butyl( ^R ,13E,14E)-35 ^- cyano- ⁷ -methyl- ⁹ -oxo-17,18-dihydro-16H- ⁵ -oxo-2 ,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane-1 ⁸ - Carboxylic acid amine (28.0mg, 0.06mmol), dioxane hydrochloride solution (4.0M) (4.0mL), added to a 25.0mL single-neck flask, reacted at room temperature for 2.0h, adjusted with saturated aqueous sodium bicarbonate solution at 0°C pH=8.0, the residue was separated with ethyl acetate (30.0 mL) and water (10.0 mL), the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by HPLC ^The compound ( ^R ,13E,14E)-35 ^- cyano- ⁷ -methyl- ⁹ -oxo-17,18-dihydro-16H- ⁵ -oxo-2, 8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane- ¹⁸ -carboxy Acid amine (Ia-3) (10.0 mg, 43% yield).

MS m/z(ESI): 388.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.34(s,1H), 7.98(s,1H), 7.88(d,1H), 7.66(s,1H), 7.76(d,1H), 7.58( s, 1H), 7.38(d, 1H), 4.32(dd, 2H), 3.94(dd, 1H), 3.85(t, 2H), 3.48(d, 1H), 3.41(dd, 1H), 3.24–3.09 (m, 2H), 1.13(d, 3H).

Example 18, (R, 1 ³ E, 1 ⁴ E)-3 ⁵ -cyano-7-methyl-9-oxo-1 ⁷ ,1 ⁸ -dihydro-1 ⁶ H-5-oxo- 2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane-1 ⁸ - Preparation of Carboxylic Acid Amines (Ib-9)

^The first step: ( ^R ,13E,14E)-35 ^- cyano- ⁷ -methyl- ⁹ -oxo-17,18-dihydro-16H- ⁵ -oxo- 2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane-1 ⁸ - Preparation of Carboxylic Acid Amines (Ib-9)

(R, ¹³ E, ¹⁴ E) ^-7 -methyl- ⁹ -oxo-17,18-dihydro-16H- ⁵ -oxo-2,8-diaza-1(5, 3)-Pyrazo[1,5-a]pyrrole[3,2-e]pyrazo[1,5-a]pyrrole[3,2-e]pyrimidine-3(1,3)-benzocyclononan Alkane-35-carbonitrile (10.0mg, 0.02mmol) was added with dichloromethane (4.0mL), 2 drops of dimethyl sulfoxide, after the solution was clear, manganese dioxide (2.0mg, 4.0mmol) was added, and the reaction was carried out at room temperature After 2.0 h, after TLC monitoring was completed, the reaction was filtered, and the filtrate was directly prepared by HPLC to obtain (R, ¹³ E, ¹⁴ E)-7-methyl-9-oxo-1 ⁸ H-5-oxo-2,8- Diaza-1(5,3)-pyrazo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-benzocyclononane ^- 35-carbonitrile (Ib -9) (6.0 mg, 66%).

MS m/z(ESI): 386.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.24(s,1H), 7.95(s,1H), 7.81(d,2H), 7.72(d,1H), 7.63(s,2H), 7.51( s, 1H), 7.32(d, 1H), 4.32(dd, 2H), 3.94(dd, 1H), 3.48(d, 1H), 3.41(dd, 1H), 1.13(d, 3H).

The beneficial effects of the present invention are demonstrated below through specific test examples.

Test Example 1. Study on the binding ability of the compounds of the present invention to the TYK2 JH2 domain

1. Experimental method

The binding ability of the compounds to the JH2 domain of TYK2 kinase was evaluated by in vitro biochemical experiments. The specific experimental steps are as follows.

The expression of the human TYK2-like kinase domain (575-869 amino acids) used was obtained by the insect cell-baculovirus expression system (Bac-to-Bac Expression System), and the specific experimental steps were carried out according to the operation manual of Invitrogen Company. Virus-infected Sf-9 insect cells for 66 hours were centrifuged using a 2.5:1 mass ratio of Buffer A solution (50 mM Hepes, pH 7.7, 500 mM NaCl, 25 mM imidazole, 5% (v/v) glycerol) with protease inhibitors added. , 0.1% Triton X-100, 0.5mM TCEP) for dissolving, and after ultrasonication, centrifugation at 9500rpm at 4° for 30 minutes, the supernatant was collected and the AKTA Explorer-100 system was used for protein purification. After the supernatant was eluted by adsorption on a nickel affinity adsorption column (50 mM Hepes, pH 7.7, 500 mM NaCl, 350 mM Imidazole, 5% (v/v) glycerol, 0.5 mM TCEP), it was further subjected to size exclusion chromatography. Purified (50mM Hepes, pH 7.7, 500mM NaCl, 1mM MnCl2, 5% (v/v) glycerol, 0.5mM TCEP), and analyzed and verified by SDS-PAGE, dynamic light scattering, liquid chromatography-mass spectrometry and other methods.

The binding ability of the compounds to the JH2 domain of the purified kinase TYK2 was tested by homogeneous time-resolved fluorescence (HTRF). A reaction system solution containing 26nM fluorescein-labeled probe and 0.2nM anti-6×His-terbium-labeled antibody (20mM Hepes pH 7.5, 150mM NaCl, 10mM was added to 10μL of His-tagged human TYK2-like kinase domain recombinant protein). MgCl2, 2mM DTT, 50μg/mL BSA, and 0.015% Brij 35) to make the final concentration of the probe 0.5nM, then add compounds with different concentration gradients, incubate at room temperature for one hour, and use a microplate reader to detect the HTRF signal. By setting a group of control group with added protein and a group of control group without protein added as a control for calculation, the IC ₅₀ value of compound competitive binding to the JH2 domain of kinase TYK2 was obtained. The smaller the IC ₅₀ value, the better the binding ability.

2. Experimental results

The _IC50 values of compounds competitively binding to the JH2 domain of the kinase TYK2 are shown in Table 1.

Table 1. _IC50 values of compounds for competitive binding to the JH2 domain of the kinase TYK2

The test results show that: the compound of the present invention has good binding ability to the TYK2 JH2 domain, the compound of the present invention can exert an allosteric regulation effect by binding to the TYK2 JH2 domain, inhibit the activity of TYK2 kinase, and be useful for preventing and/or treating related to TYK2 potential for autoimmune diseases such as psoriasis, systemic lupus erythematosus, inflammatory bowel disease, etc.

Test Example 2. The ability of the compounds of the present invention to inhibit pSTAT5 in human peripheral blood mononuclear cells (PBMC) induced by IFNa

1. Experimental method

The inhibitory ability of compounds on TYK2 signaling pathway in human PBMC cells was evaluated by in vitro cell experiments. The specific experimental steps are as follows.

Human PBMC cells were plated in a 96-well plate, and compound diluted in DMSO was added, and incubated at 37°C for 60 minutes. Add 20ng/mL of IFN-a to stimulate cells and incubate at 37°C for 15 minutes. Add 1 μL of anti-human CD3 antibody to each well and incubate at 4 degrees Celsius for 30 minutes. Transfer the cells to a 96-well deep-well plate, add 1 mL of fixative to each well, shake to mix, and incubate in a 37-degree water bath for 10 minutes. Centrifuge at 600g for 5 minutes, rinse with PBS, add 1000 μL of Perm III to each well, incubate at 4 degrees Celsius for 30 minutes, and centrifuge. Cells were resuspended in FACS buffer (PBS+0.2%BSA+1mM EDTA) and centrifuged. Incubate with human pSTAT5 antibody for 40 minutes at room temperature. Cells were washed twice with FACS buffer. Add 1 mL of FACS buffer to each tube and use flow cytometry to detect.

2. Experimental results

Table 2 shows the inhibitory activity of the compounds of the present invention on pSTAT5 in PBMC cells.

Table 2. Inhibitory activity of compounds of the present invention on pSTAT5 in PBMC cells

化合物编号Compound number	pSTAT5 IC ₅₀(nM) pSTAT5 _IC50 (nM)
la-8la-8	3.553.55
lb-3lb-3	2.212.21

In a variety of autoimmune diseases including psoriasis, IBD, and systemic lupus erythematosus, a variety of pathogenic cytokines play an important role through the JAK/STAT signaling pathway. Type I interferons (IFNα, IFNβ, etc.), IL-12, IL-23, etc. activate downstream STATs (STAT1, STAT2, STAT3, STAT5) through TYK2 to complete signal transduction. The results of this test show that the compound of the present invention has a good inhibitory effect on pSTAT5 in IFNα-induced PBMC cells, further indicating that the compound of the present invention can volatilize the inhibitory effect on TYK2, and be used for the prevention and/or treatment of TYK2-related diseases.

Test Example 3. The ability of the compounds of the present invention to inhibit IFNa-induced pSTAT5 in human whole blood

1. Experimental method

The inhibitory ability of compounds on TYK2 signaling pathway in human whole blood cells was evaluated by in vitro cell experiments. The specific experimental steps are as follows.

Human whole blood cells were plated in a 96-well plate, and compounds serially diluted in DMSO were added, and incubated at 37°C for 60 minutes. Add 20ng/mL of IFN-a to stimulate cells and incubate at 37°C for 15 minutes. Add 1 μL of anti-human CD3 antibody to each well and incubate at 4 degrees Celsius for 30 minutes. Transfer the cells to a 96-well deep-well plate, add 1 mL of fixative to each well, shake to mix, and incubate in a 37-degree water bath for 10 minutes. Centrifuge at 600g for 5 minutes, rinse with PBS, add 1000 μL of Perm III to each well, incubate at 4 degrees Celsius for 30 minutes, and centrifuge. Cells were resuspended in FACS buffer (PBS+0.2%BSA+1mM EDTA) and centrifuged. Incubate with human pSTAT5 antibody for 40 minutes at room temperature. Cells were washed twice with FACS buffer. Add 1 mL of FACS buffer to each tube and use flow cytometry to detect.

2. Experimental results

Table 3 shows the inhibitory activity of the compounds of the present invention on pSTAT5 in human whole blood cells.

Table 3. Inhibitory activity of compounds of the present invention on pSTAT5 in human whole blood cells

化合物编号Compound number	pSTAT5 IC ₅₀(nM) pSTAT5 _IC50 (nM)
la-8la-8	34.4834.48
lb-3lb-3	38.8738.87

The same as Test Example 2, the test results show that the compounds of the present invention have a good inhibitory effect on pSTAT5 in human whole blood cells induced by IFNα, and further illustrate that the compounds of the present invention can volatilize the inhibitory effect on TYK2, and be used for the prevention and/or treatment of TYK2. related diseases.

Test Example 4. The compounds of the present invention inhibit the activity of JAK1, JAK2, JAK3, TYK2 and JH1

1. Experimental method

The inhibitory effect of the compounds and purified kinases JAK1, JAK2, JAK3, TYK2 kinases on the kinase activity of the JH1 domain of the kinases was detected by homogeneous time-resolved fluorescence (HTRF). Prepare a 1× assay buffer. Compounds were diluted three-fold in DMSO, and 100 nL of compound solution was added to each well of a 384-well plate at each gradient point. Dilute JAK1 JH1, JAK2 JH1, JAK3 JH1 and TYK2 JH1 with 1×assay buffer, add 5 μL per well to a 384-well plate, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 15 minutes. Use 1×assay buffer to prepare the substrate solution, add 5 μL per well to a 384-well plate, and centrifuge at 1000 rpm for 30 seconds. The 384-well plates of JAK1 JH1 and JAK2 JH1 were incubated at room temperature for 45 minutes, respectively, and the 384-well plates of JAK3 JH1 and TYK2 JH1 were incubated at room temperature for 60 minutes, respectively. 10 μL of reaction detection solution was added to each well, and the 384-well plates of JAK1 JH1 and JAK2 JH1 were incubated at room temperature for 60 minutes, respectively, and the 384-well plates of JAK3 JH1 and TYK2 JH1 were incubated at room temperature for 120 minutes respectively, and the HTRF signal was detected by a microplate reader. By setting a group of control group with added protein and a group of control group without protein added as a control for calculation, the _IC50 values of compounds inhibiting the kinase activities of JAK1 JH1, JAK2 JH1, JAK3 JH1 and TYK2 JH1 were obtained respectively.

2. Experimental results

The results of inhibitory activity of the compounds of the present invention on JAK1 JH1, JAK2 JH1, JAK3 JH1 and TYK2 JH1 are shown in Table 4.

Table 4. Compounds against JAK1 JH1, JAK2 JH1, JAK3 JH1 and TYK2 JH1 inhibitory activity

Due to the high homology of JAK family members in the ATP-binding pocket, JAK inhibitors targeting the JH1-binding domain of JAK tend to have high side effects. By targeting the TYK2 JH2 binding domain, the compound of the present invention has no binding activity to JAK family kinases including the JH1 domain of TYK2, has high selectivity, and can effectively avoid off-target effects.

Test Example 5. Study on the binding ability of the compounds of the present invention to the JAK1 JH2 domain

1. Experimental method

The in vitro biochemical experiments were used to evaluate the binding ability of the compounds to the JH2 domain of the JAK1 kinase. The specific experimental steps are as follows.

The binding ability of the compounds to the JH2 domain of the purified kinase JAK1 was tested by homogeneous time-resolved fluorescence (HTRF). Prepare a 1× assay buffer. Compounds were diluted three-fold in DMSO, and 75nL of compound solution was added to each well of a 384-well plate at each gradient point. Dilute JAK1 JH2 with 1×assay buffer, add 5 μL per well to a 384-well plate, and centrifuge at 1000 rpm for 30 seconds. Dilute Tb-antibody with 1×assay buffer, add 5 μL per well to a 384-well plate, and centrifuge at 1000 rpm for 30 seconds. Dilute Tracer with 1×assay buffer, add 5 μL per well to a 384-well plate, and centrifuge at 1000 rpm for 30 seconds. Incubate at room temperature for one hour, then incubate overnight at 4°C, and use a microplate reader to detect the HTRF signal. By setting a group of control group with added protein and a group of control group without protein added as a control for calculation, the IC ₅₀ value of the compound competitively binding to the JH2 domain of the kinase JAK1 was obtained.

2. Experimental results

The results of the study on the binding ability of the compounds of the present invention to the JAK1 JH2 domain are shown in Table 5.

Table 5. Binding ability of compounds to JAK1 JH2 domain

The current JAK inhibitors all have the disadvantage of low selectivity. The compounds of the present invention can effectively inhibit TYK2 kinase activity through allosteric effect, have high selectivity, and can effectively avoid off-target effects.

In conclusion, the compounds of the present invention have a good inhibitory effect on TYK2, and can be used to treat diseases related to TYK2 kinase dysfunction, such as cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, and respiratory diseases. and heart disease. At the same time, the compound of the present invention has high selectivity for the TYK2 JH2 binding domain, is safe when used, and has little toxic and side effects. The compounds of the present invention can be used for preparing TYK2 inhibitors and medicines for treating diseases related to TYK2 kinase dysfunction, and have good application prospects.

Claims

The compound represented by formula I, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate:

in,

L is a linker of 1-20 atoms; the linker is independently selected from -O-, -S-, -NR a -, -CR c R d -, -S(=O)-, -S(=O ) 2 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR a -, -OC(=O)NR a -, - NR a C(=O)NR b -, -NR b C(=O)-, -NR b C(=O)O-,
alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocycloalkyl, aryl, or heteroaryl is independently substituted with zero, one, or more Ra ; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl two R a on the same carbon atom or adjacent carbon atoms in a radical or heteroaryl group form an epoxy group, a cycloalkyl group, a heterocycloalkyl group,

Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;

R Z is selected from hydrogen or alkyl;

L 1 and L 2 are independently selected from alkyl or alkyl substituted by one or more RL ;

R L is independently selected from halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS (=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R, -OC(=O)R a , -C(=O)OR b , -C(= O) NRcRd ,-OC(=O) NRcRd , -NRbC (=O ) NRcRd , -NRbC ( =O) Ra , -NRbC ( =O) OR b , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two RLs of the same carbon atom form a ring oxy, cycloalkyl or heterocycloalkyl; or two R L of two adjacent carbon atoms form cycloalkyl or heterocycloalkyl;

R 1 is selected from hydrogen, alkyl or haloalkyl;

Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

is a single bond or a double bond;

R A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , - NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O )OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O) R a , -NR b C(=O)OR b , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R A1 ; or each alkyl, alkenyl, alkynyl, cycloalkane group, heterocycloalkyl, aryl or heteroaryl, two R A1 on the same carbon atom or adjacent carbon atoms form epoxy, cycloalkyl, heterocycloalkyl,

n is an integer of 0, 1, 2, 3 or 4;

R 2 , R 3 , R A1 are independently selected from hydrogen, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(= O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or the same Two R A1 on carbon atoms form =O, cycloalkyl or heterocycloalkyl;

R a is independently selected from alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkene group, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl independently consisting of one or more halogen, -CN, -OH, -OMe, -NH2 , -C(=O)Me, -COOH, -COOMe, alkyl or haloalkyl substitution;

R b is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl independently consisting of one or more halogen, -CN, -OH, -Me, -NH2 , -C(=O) Me, -COOH, -COOMe, alkyl or haloalkyl substitution;

R c and R d are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is independently composed of one or more halogen, -CN, -OH, -Me, -NH2 , -C( =O) Me, -COOH, -COOMe, alkyl or haloalkyl substitution; or a heterocycloalkyl group consisting of R c and R d and a nitrogen atom, the heterocycloalkyl group consisting of halogen, -CN, -OH, -Me , -NH2 , -C(=O)Me, -COOH, -COOMe, alkyl or haloalkyl substituted.
The compound according to claim 1, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, is characterized in that:

L is a linker of 1-20 atoms; the linker is independently selected from -O-, -S-, -NR a -, -CR c R d -, -S(=O)-, -S(=O ) 2 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR a -, -OC(=O)NR a -, - NR a C(=O)NR b -, -NR b C(=O)-, -NR b C(=O)O-,
C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl independently consists of zero, One or more Ra substitutions; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is formed by two Ra on the same or adjacent carbon atoms Epoxy, cycloalkyl, heterocycloalkyl,

Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;

R Z is selected from hydrogen or C 1 -C 6 alkyl;

L 1 and L 2 are independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more RL ;

R L is independently selected from halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS (=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R, -OC(=O)R a , -C(=O)OR b , -C(= O) NRcRd ,-OC(=O) NRcRd , -NRbC (=O ) NRcRd , -NRbC ( =O) Ra , -NRbC ( =O) OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R L of the same carbon atom form epoxy, cycloalkyl or heterocycloalkyl; or two adjacent carbon atoms Two R L form a cycloalkyl or heterocycloalkyl;

R 1 is selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

is a single bond or a double bond;

R A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , - NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O )OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O) R a , -NR b C(=O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R A1 ; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is on the same or adjacent carbon atoms Two R A1 on the atom form epoxy, cycloalkyl, heterocycloalkyl,

n is an integer of 0, 1, 2, 3 or 4;

R 2 , R 3 , R A1 are independently selected from hydrogen, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(= O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R A1 on the same carbon atom form =O, cycloalkyl or heterocycloalkyl ;

R a is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 ~C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl independently composed of one or more halogen, -CN, -OH, -OMe, -NH 2 , -C(=O)Me, -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkane base substitution;

R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl Aryl independently consists of one or more halogens, -CN, -OH, -Me, -NH 2 , -C(=O)Me, -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl substitution;

R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl The radical or heteroaryl is independently composed of one or more halogen, -CN, -OH, -Me, -NH2 , -C(=O)Me, -COOH, -COOMe, C1 - C6 alkyl or C 1 -C 6 haloalkyl substitution; or a heterocycloalkyl group consisting of R c and R d and a nitrogen atom, the heterocycloalkyl group is composed of halogen, -CN, -OH, -Me, -NH 2 , -C(=O ) Me, -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl substitution.
The compound according to claim 2, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, is characterized in that:

L is a linker of 1-10 atoms, and the linker is independently selected from -O-, -S-, -NR a -, -CR c R d -, -S(=O)-, -S(=O ) 2 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR a -, -OC(=O)NR a -, - NR a C(=O)NR b -, -NR b C(=O)-, -NR b C(=O)O-,
C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl independently consists of zero, One or more Ra substitutions; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is formed by two Ra on the same or adjacent carbon atoms
Cycloalkyl, Heterocycloalkyl,

Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;

R Z is selected from hydrogen or C 1 -C 6 alkyl;

L 1 and L 2 are independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more RL ;

R L is independently selected from halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS (=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R, -OC(=O)R a , -C(=O)OR b , -C(= O) NRcRd ,-OC(=O) NRcRd , -NRbC (=O ) NRcRd , -NRbC ( =O) Ra , -NRbC ( =O) OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R L of the same carbon atom form epoxy, cycloalkyl or heterocycloalkyl; or two adjacent carbon atoms Two R L form a cycloalkyl or heterocycloalkyl;

R 1 is selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

is a single bond or a double bond;

R A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , - NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O )OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O) R a , -NR b C(=O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted with one or more R A1 ; or each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is on the same or adjacent carbon atoms Two R A1s on an atom form

Cycloalkyl, Heterocycloalkyl,

n is an integer of 0, 1, 2, 3 or 4;

R 2 , R 3 , R A1 are independently selected from hydrogen, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(= O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R A1 on the same carbon atom form =O, cycloalkyl or heterocycloalkyl ;

R a is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 ~C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl independently composed of one or more halogen, -CN, -OH, -OMe, -NH 2 , -C(=O)Me, -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkane base substitution;

R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl Aryl independently consists of one or more halogens, -CN, -OH, -Me, -NH 2 , -C(=O)Me, -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl substitution;

R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl The radical or heteroaryl is independently composed of one or more halogen, -CN, -OH, -Me, -NH2 , -C(=O)Me, -COOH, -COOMe, C1 - C6 alkyl or C 1 -C 6 haloalkyl substitution; or a heterocycloalkyl group consisting of R c and R d and a nitrogen atom, the heterocycloalkyl group is composed of halogen, -CN, -OH, -Me, -NH 2 , -C(=O ) Me, -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl substitution.
The compound according to claim 1, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, is characterized in that:

L is selected from

Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;

R Z is selected from hydrogen or C 1 -C 6 alkyl;

L 1 and L 2 are independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more RL ;

R L is independently selected from halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS (=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R, -OC(=O)R a , -C(=O)OR b , -C(= O) NRcRd ,-OC(=O) NRcRd , -NRbC (=O ) NRcRd , -NRbC ( =O) Ra , -NRbC ( =O) OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R L of the same carbon atom form epoxy, cycloalkyl or heterocycloalkyl; or two adjacent carbon atoms Two R L form a cycloalkyl or heterocycloalkyl;

Preferably, Z 1 and Z 2 are independently selected from -O- or -NR Z -; R Z is selected from hydrogen or C 1 -C 6 alkyl; L 1 and L 2 are independently selected from C 1 -C 6 alkane base;

More preferably, Z 1 and Z 2 are independently selected from -O- or -NR Z -; R Z is selected from hydrogen; L 1 and L 2 are independently selected from C 1 -C 6 alkyl groups;

Further preferably, L is selected from
The compound according to claim 1, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, is characterized in that:

Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-one, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, indazole base, azaindolyl, benzimidazolyl, benzotriazaazolyl, benzofuranyl, benzothiazolebenzoxazolyl, benzisoxazolyl, benzothienyl, naphthyl.
The compound according to claim 1, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, is characterized in that:

R A is independently selected from hydrogen, halogen, amino, mercapto, nitro, hydroxyl, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , - NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O )OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O) R a , -NR b C(=O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2- C6alkynyl , 3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; wherein each alkyl, alkenyl, alkynyl, 3- 6-membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl independently substituted by one or more R A1 ; or each alkyl, alkenyl, alkynyl, 3-6 membered cycloalkane two RAs on the same carbon atom form a 3- to 6-membered epoxy group, a 3- to 6-membered cycloalkyl group or a pyrrolidinyl group; or adjacent Two RAs on carbon atoms form 3-6 membered cycloalkyl or pyrrolidinyl;

R 2 , R 3 , R A1 are independently selected from hydrogen, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O) 2 R a , -NO 2 , -NR c R d , -NHS(=O) 2 R a , -S(=O) 2 NR c R d , -C(=O)R a , -OC(=O)R a , -C(= O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; or two R A1 on the same carbon atom form =O, 3-6 membered cycloalkyl or pyrrolidinyl;

R a is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 ~C alkynyl, 3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; wherein each alkyl, alkenyl, alkynyl, 3-6 membered cycloalkyl , pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl independently consisting of one or more halogens, -CN, -OH, -OMe, -NH2 , -C(=O)Me, -COOH, - COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl substitution;

R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furyl, pyridyl or pyrimidinyl; wherein, each alkyl, alkenyl, alkynyl, 3-6 membered ring Alkyl, pyrrolidinyl, phenyl, furanyl, pyridinyl or pyrimidinyl independently consisting of one or more halogen, -CN, -OH, -Me, -NH2 , -C(=O)Me, -COOH , -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl substitution;

R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2- C6alkynyl , 3-6 membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl; wherein each alkyl, alkenyl, alkynyl, 3- 6-membered cycloalkyl, pyrrolidinyl, phenyl, furanyl, pyridyl or pyrimidinyl independently consisting of one or more halogen, -CN, -OH, -Me, -NH2 , -C(=O)Me , -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or R c and R d and nitrogen atoms form a pyrrolidinyl group consisting of halogen, -CN, - OH, -Me, -NH 2 , -C(=O)Me, -COOH, -COOMe, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl substitution;

Preferably, the 3-6 membered epoxy group is selected from
The compound according to any one of claims 1 to 6, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, characterized in that: The compound is shown in formula Ia:

wherein, L, R 1 , R 2 , R 3 , A ring, n and RA are as described in any one of claims 1 to 6;

Alternatively, the compound is shown in formula Ib:

wherein L, R 1 , R 2 , R 3 , A ring, n and RA are as described in any one of claims 1 to 6 .
The compound according to any one of claims 1 to 6, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, characterized in that: The compound is shown in formula II:

wherein, R 1 , R 2 , R 3 , A ring, n and R A are as described in any one of claims 1 to 6;

is a single bond or a double bond;

Preferably, the compound is shown in formula III:

wherein, A ring, n and R A are as described in any one of claims 1 to 6;

is a single bond or a double bond;

More preferably, the compound is shown in formula IV:

wherein, n and RA are as described in any one of claims 1 to 6;

X and Y are independently selected from N or CR B ; and X and Y are not N at the same time; RB is selected from hydrogen or C 1 -C 6 alkyl;

is a single bond or a double bond;

Further preferably, the compound is shown in formula IVa:

wherein, n and RA are as described in any one of claims 1 to 6;

is a single bond or a double bond;

Alternatively, the compound is shown in formula IVb:

wherein, n and RA are as described in any one of claims 1 to 6;

is a single bond or a double bond;

Alternatively, the compound is shown in formula IVc:

wherein, n and RA are as described in any one of claims 1 to 6;

single or double bond.
The compound according to any one of claims 1 to 6, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, characterized in that: The compound is one of the following compounds:
A method for preparing the compound described in claim 8 or 9, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, characterized in that: It includes the following steps:
The compound described in any one of claims 1 to 9, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, in the preparation of a TYK2 inhibitor drug and/or, in the preparation of a medicament for a disease associated with TYK2 kinase dysfunction;

Preferably, the disease is an inflammatory disease, autoimmune disease, hyperproliferative disease in mammals, cancer, bone disease, neurological disease, metabolic disease, respiratory disease and/or heart disease;

More preferably, the inflammatory and autoimmune diseases are rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease;

Further preferably, the inflammatory bowel disease is ulcerative colitis and Crohn's disease.
A pharmaceutical composition, which is a compound according to any one of claims 1 to 9, or a stereoisomer, or a solvate, or a salt, or an ester, or a prodrug, or a prodrug thereof. Hydrates are preparations prepared from active ingredients and pharmaceutically acceptable excipients or auxiliary ingredients;

Preferably, the pharmaceutically acceptable adjuvant or auxiliary ingredient is one or more pharmaceutically acceptable carriers, diluents or excipients.