TW202227430A - Nitrogen-containing derivatives, their preparation method and their medical use - Google Patents

Abstract

The present disclosure relates to nitrogen-containing heterocyclic derivatives, their preparation method and their medical use. Specifically, the present disclosure relates to a nitrogen-containing heterocyclic derivative represented by the general formula (I), its preparation method, a pharmaceutical composition containing the same, and its use as a therapeutic agent, especially as a TYK2 inhibitor and the use in the preparation of medicaments for the treatment and/or prevention of inflammatory and autoimmune diseases.

Description

Nitrogen-containing heterocyclic derivatives, their preparation method and their application in medicine

The present disclosure belongs to the field of medicine, and relates to a nitrogen-containing heterocyclic derivative, its preparation method and its application in medicine. In particular, the present disclosure relates to the nitrogen-containing heterocyclic derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, as well as their use as TYK2 inhibitors and their preparation for treatment Use in a medicament for the prevention of inflammatory diseases or autoimmune diseases.

Cytokine signaling plays a key role in controlling the growth, differentiation, function, and communication of immune cells. The actions of receptor-bound Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) mediate multiple cytokine signaling pathways (Cooper, GS et al., "Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases” J. Autoimmun. 2009, 33: 197-207; Schwartz DM et al., “JAK inhibition as a therapeutic strategy for immune and inflammatory diseases” Nat Rev Drug Discov. 2017, 17: 78; Schwartz DM et al., "Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases" Nat Rev Rheumatol. 2016, 12:25-36).

JAKs are a family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) associated with the intracellular domain of cell surface cytokine receptors. Upon stimulation and oligomerization of these receptors, JAK molecules are activated and phosphorylate receptor tyrosine residues to serve as docking sites for subsequent recruitment and phosphorylation of STAT proteins. Phosphorylated STAT proteins, in turn, dimerize, translocate to the nucleus and activate transcription of genes that mediate cytokine-induced responses. These cytokine-mediated JAK/STAT pathways are tightly regulated, and dysfunctional JAK/STAT activity has been shown to be a hallmark of many immune and autoimmune diseases, inflammatory diseases, and cellular transformation (Schwartz DM et al., "JAK inhibition as a therapeutic strategy for immune and inflammatory diseases” Nat Rev Drug Discov. 2017, 17: 78).

Tyrosine kinase 2 (TYK2), the first identified member of the JAK family, is a component of various cytokine pathways leading to STAT-dependent gene transcription and cytokine-specific functional responses, including the interleukin 12/-23 family ( IL-12/IL-23, with a common p40 subunit), the type I interferon (IFN) family, and the IL-6 and IL-10 families (Schwartz DM et al., "Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases” Nat Rev Rheumatol. 2016, 12: 25-36). TYK2-mediated cytokine signaling plays a key role in the pathogenesis of autoimmune and inflammatory diseases. Specifically, IL-23 (a heterodimer containing p40 and p19 subunits) is essential for the differentiation and proliferation of T helper cells 17 (Th17), which are critically involved in several autoimmune diseases (Aggarwal, S et al., "Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17" J Biol Chem. 2003, 278: 1910-1914). IL-12, consisting of p40 and a unique p35 subunit, plays an important role in regulating Th1 development and IFN-γ secretion by these cells (Metzger DW at al., "Interleukin-12 acts as an adjuvant for humoral immunity through interferon" -gamma-dependent and -independent mechanisms" Eur J Immunol. 1997, 27: 1958-65). By mediating Th1/Th17 responses, IL-12 and IL-23 play a role in various inflammatory diseases [eg psoriasis/psoriasis (Ps), lupus, inflammatory bowel disease (IBD), multiple sclerosis (MS), (Michele WL T et al., "IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases" Nat Med. 2015,21 : 719-729; Andrew LC et al., "IL-23: One cytokine in control of autoimmunity" Eur. J. Immunol. 2012, 42: 2263-2273; Craig AM et al., "Divergent Pro-and Anti- Inflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation" J. Exp. Med. 2003, 198: 1951-1957). For example, in mouse models, blockade or deletion of the common subunit P40 of IL-12 and IL-23 or the common receptor IL23R was found to protect mice from various autoimmune diseases (psoriasis/psoriasis, lupus, Inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, etc.) (Kyttaris VC et al., "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice" 2010, 184: 4605-9 ; Paulina K et al., “IL-12 protects from psoriasiform skin inflammation” Nat Commun. 2016, 7: 13466; Hong K et al., “IL-12, independent of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder" J Immunol. 1999, 162:7480-91). In human disease, high levels of IL-12 and IL-23 are observed in the lesional skin of patients with psoriasis, and then levels decrease after various treatments of psoriasis (Lee E at al., “Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris" J Exp Med. 2004, 199: 125-30). In addition, monoclonal antibodies that block IL-12/IL-23 common subunit p40 (Ustekinumab, Briakinumab, etc.) or IL-23-specific subunit p19 (Tildrakizumab, Risankizumab, etc.) have been shown to be clinically useful in the treatment of psoriasis Efficacy, Crohn's disease et al. (Gandhi M at al., "Anti-p40 antibodies ustekinumab and briakinumab: blockade of interleukin-12 and interleukin-23 in the treatment of psoriasis" Semin Cutan Med Surg. 2010 , 29: 48- 52; Bram V et al., “New treatment options for inflammatory bowel diseases” J Gastroenterol. 2018, 53: 585). At the same time, members of the type I IFN family (IFN-α, -β, -ε, -κ, -, etc.) that function through the heterodimeric IFN receptor (IFNAR) are important mediators of innate and adaptive immunity, At the same time, it can also activate various elements in the immune response and enhance the expression and release of self-antigens, thus becoming a key player in the expansion of autoimmune diseases (Lionel BI et al., "Regulation of type I interferon responses" Nat Rev Immunol. 2014, 14 : 36-49; John CH et al., "Type I interferons: cruel participants in disease amplification in autoimmunity" Nat Rev Rheumatol. 2010, 6: 40-49; Antonios P et al., "Type I interferon-mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy” Rheumatology 2017, 10: 1662-1675). The importance of type I IFN in the pathogenesis of systemic lupus erythematosus (SLE) has been demonstrated experimentally, and IFNAR depletion largely reduces disease severity and disease mortality in a lupus-susceptible NZB mouse model (Santiago -Raber ML et al., "Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice" J Exp Med. 2003, 197:777-88). In human SLE patients, elevated serum IFNα levels and elevated expression levels of type I IFN regulatory genes in peripheral blood mononuclear cells (PBMCs) and affected organs were found in many patients. In addition, other studies have also reported that the activation of type I interferon is closely related to the disease severity of SLE (Bengtsson AA et al., "Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies" Lupus. 2000, 9:664-71).

Multiple studies have demonstrated the importance of TYK2 in the pathogenesis of the aforementioned autoimmune diseases. For example, rodents in which TYK2 is inactivated or chemically inhibited in vivo have been found to exhibit disease resistance in experimental autoimmune disease models such as psoriasis, multiple sclerosis, and inflammatory bowel disease (Michael P. Set al., "The Interleukin -23/Interleukin-17 Axis Links Adaptive and Innate Immunity in Psoriasis” Front. Immunol . 2018, 10: 3389; Ishizaki M et al., “Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23 /Th17 axes in vivo." J Immunol. 2011, 187: 181-9). Population studies have found reduced SLE in children and adults carrying TYK2 activity-deficient variants such as rs12720356 and rs34536443 in the Mexican Mestizo population (Cecilia CC et al., "Catalytically Impaired TYK2 Variants are Protective Against Childhood- and Adult-Onset" Systemic Lupus Erythematosus in Mexicans” Scientific Reports. 2019, 9:12165). In addition, TYK2 SNP mutations have also been reported to be associated with SLE in Nordic, British, and Chinese Han populations. Genome-wide association studies (GWAS) found several active loss-of-function variants of TYK2 were significantly associated with resistance to inflammatory diseases, including multiple sclerosis, psoriasis, Crohn's disease, lupus, and rheumatoid arthritis, further suggesting that TYK2 Has an important role in a wide range of autoimmune diseases. (Westra HJ et al., “Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes” Nat Genet. 2018, 50: 1366-1374; Okada Y et al., “Genetics of rheumatoid arthritis contributes to biology and drug discovery” Nature. 2014, 506: 376-81; Mero IL et al., “A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis” Eur J Hum Genet. 2010, 18: 502-4 ; Peluso C et al., “TYK2 rs34536443 polymorphism is associated with a decreased susceptibility to endometriosis-related infertility” Hum Immunol. 2013, 74: 93-7; Gorman JA et al., “The TYK2-P1104A autoimmune protective variant limits coordinate limits signals required to generate specialized T cell subsets” Front Immunol. 2019, 25;10:44). Thus, the development of drugs that inhibit TYK2-mediated cytokine signaling pathways has potential therapeutic benefits for human autoimmune diseases. Indeed, BMS986165, a highly selective allosteric TYK2 inhibitor, has been shown to effectively block IL-12/IL-23 and type I IFN signaling pathways, resulting in IBD) showed significant efficacy (Tokarski JS et al., "Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain" J Biol Chem. 2015, 290: 11061-74). In addition, Phase 2 clinical trial results reported that the drug met the primary endpoint of efficacy in patients with moderate-to-severe plaque psoriasis with a favorable risk-benefit ratio. After taking BMS986165 for 12 weeks, the Psoriasis Area and Severity Index scores decreased by more than 75% (PASI 75) in most patients, and by more than 90% in some patients (PASI 90) (Kim P. et al., "Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis” N Engl J Med. 2018, 379: 1313-1321), which further illustrates the effectiveness and potential of TYK2 as a target in the field of autoimmune disease treatment.

Published patent applications for TYK2 inhibitors include WO2014074661A1, WO2020086616A1, WO2020092196A1, WO2020156311A1 and the like.

The object of the present disclosure is to provide a compound represented by the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its tautomer, racemate, enantiomer, or mixture thereof. Medicinal salt:

in,

、

、

、

和

R ¹ is selected from

,

,

,

and

wherein L is the same or different at each occurrence, and each is independently selected from a bond, ( _CH2 ) _q , C(O), NH, and an oxygen atom;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁸ is the same or different at each occurrence and is each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, haloalkyl, pendant oxy, halogen, cyano, -NR ^dd R substituted with one or more substituents in ^ee , nitro, ^-ORcc , cycloalkyl, heterocyclyl, aryl and heteroaryl;

的雜環基，其中S原子作為雜環基中的 環原子； Ring C is containing at least one

The heterocyclyl group, wherein the S atom is used as the ring atom in the heterocyclyl group;

R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom, a pendant oxy group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, -OR ^c , a hydroxyalkyl group, a cyano group, -NR ^{d Re} and nitro;

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ² is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, nitro, -OR ^c , -S(O) _r R ^c , -NR ^{d Re} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C (O)OR ^c , -OC(O)OR ^c , -OC(O)NR ^{d Re} , -C(O)NR ^{d Re} , -NR ^f C(O)NR ^{d Re} , -NR ^f C (O) ^Rc , ^-NRfC (O) ^ORc , -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -(CH ₂ ) _p -heteroaryl groups are each independently optionally selected from a hydrogen atom, a pendant oxy group, a halogen, an alkyl group, a haloalkyl group, -OR ^cc , -NR ^dd R ^ee , -C(O)R ^cc , - ^substituted with one or more substituents of OC(O) ^Rcc , -C(O) ^ORcc , -C(O) ^NRddRee , cyano and nitro;

R ³ is selected from alkyl, haloalkyl, -OR ^c , -S(O) _r R ^c , -NR ^f S(O) _r R ^c , -(CH ₂ ) _p -cycloalkyl, -(CH ₂ ) _p -heterocyclyl, -( _CH2 ) _p -aryl and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl are each independently optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, ^-ORcc , Substituted with one or more substituents of cyano, -NR ^dd R ^ee , nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ⁴ is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, nitro, -OR ^c , -S(O) _r R ^c , -NR ^{d Re} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C (O)OR ^c , -OC(O)OR ^c , -OC(O)NR ^{d Re} , -C(O)NR ^{d Re} , -NR ^f C(O)NR ^{d Re} , -NR ^f C (O)R ^c and -NR ^f C(O)OR ^c ;

X and Y are the same or different, and are each independently an N atom or CR ^x ;

Rx ^is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, ^-ORc , cyano, nitro, -S(O ⁾ _rRc ^{, -NRdRe} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C(O)OR ^c , -OC( O) ^ORc , -OC(O) ^NRdRe , -C(O) ^NRdRe , ^-NRfC (O) ^NRdRe , ^{-NRfC ( O )Rc and -NRf} C(O)OR ^c ; wherein the alkyl group is optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, -OR ^cc , cyano, -NR ^dd R ^ee , nitro, cycloalkyl, hetero substituted with one or more substituents in cyclic, aryl and heteroaryl;

R ^6a and R ^6b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -C(O)R ^c , -(CH ₂ ) _p - Cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -ring Alkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl are each independently optionally selected from hydrogen atoms, pendant oxy groups, halogens , alkyl, haloalkyl, hydroxyalkyl, -OR ^cc , cyano, -NR ^dd R ^ee , nitro, cycloalkyl, heterocyclyl, aryl, and one or more substituents in heteroaryl replaced;

R ^7a and R ^7b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group , aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups , cyano, -NR ^dd R ^ee , nitro, -OR ^cc , cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;

^R5 , ^R9 , and ^Rf are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, -OR ^cc , cyano, - Substituted with one or more substituents in NR ^{dd Ree} , nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^c and R ^cc are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; wherein , the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, cyano, -NR ^dd R ^ee , nitro substituted with one or more substituents in radicals, cycloalkyls, heterocyclyls, aryls and heteroaryls;

R ^d , R ^e , R ^dd and R ^ee are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, cyano, nitro , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2 or 3;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 1, 2, 3, 4, 5 or 6;

r is 0, 1 or 2;

s is 0, 1, 2, 3, 4, or 5; and

t is 0, 1, 2, 3, 4 or 5.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,

、

、

、

和

R ¹ is selected from

,

,

,

and

wherein L is the same or different at each occurrence, and each is independently selected from a bond, ( _CH2 ) _q , C(O), NH, and an oxygen atom;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁸ is the same or different at each occurrence and is each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, haloalkyl, pendant oxy, halogen, cyano, -NR ^dd R substituted with one or more substituents in ^ee , nitro, ^-ORcc , cycloalkyl, heterocyclyl, aryl and heteroaryl;

的雜環基，其中S原子作為雜環基中的 環原子； Ring C is containing at least one

The heterocyclyl group, wherein the S atom is used as the ring atom in the heterocyclyl group;

R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom, a pendant oxy group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, -OR ^c , a hydroxyalkyl group, a cyano group, -NR ^{d Re} and nitro;

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ² is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, nitro, -OR ^c , -S(O) _r R ^c , -NR ^{d Re} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C (O)OR ^c , -OC(O)OR ^c , -OC(O)NR ^{d Re} , -C(O)NR ^{d Re} , -NR ^f C(O)NR ^{d Re} , -NR ^f C (O) ^Rc , ^-NRfC (O) ^ORc , -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -(CH ₂ ) _p -heteroaryl groups are each independently optionally selected from a hydrogen atom, a pendant oxy group, a halogen, an alkyl group, a haloalkyl group, -OR ^cc , -NR ^dd R ^ee , -C(O)R ^cc , - ^substituted with one or more substituents of OC(O) ^Rcc , -C(O) ^ORcc , -C(O) ^NRddRee , cyano and nitro;

R ³ is selected from alkyl, haloalkyl, -OR ^c , -S(O) _r R ^c , -NR ^f S(O) _r R ^c , -(CH ₂ ) _p -cycloalkyl, -(CH ₂ ) _p -heterocyclyl, -( _CH2 ) _p -aryl and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl are each independently optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, ^-ORcc , Substituted with one or more substituents of cyano, -NR ^dd R ^ee , nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Each R ⁴ is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, nitro, -OR ^c , -S(O) _r R ^c , -NR ^{d Re} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C (O)OR ^c , -OC(O)OR ^c , -OC(O)NR ^{d Re} , -C(O)NR ^{d Re} , -NR ^f C(O)NR ^{d Re} , -NR ^f C (O)R ^c and -NR ^f C(O)OR ^c ;

R ⁵ , R ⁹ , R ^c , R ^cc , R ^d , ^Re , R ^f , R ^dd and R ^ee are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from hydrogen atoms , halogen, alkyl, haloalkyl, -OR ^cc , cyano, -NR ^dd R ^ee , nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents ;

X and Y are the same or different, and are each independently an N atom or CR ^x ;

Rx ^is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, ^-ORc , cyano, nitro, -S(O ⁾ _rRc ^{, -NRdRe} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C(O)OR ^c , -OC( O) ^ORc , -OC(O) ^NRdRe , -C(O) ^NRdRe , ^-NRfC (O) ^NRdRe , ^{-NRfC ( O )Rc and -NRf} C(O)OR ^c ; wherein the alkyl group is optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, -OR ^cc , cyano, -NR ^dd R ^ee , nitro, cycloalkyl, hetero substituted with one or more substituents in cyclic, aryl and heteroaryl;

R ^6a and R ^6b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -C(O)R ^c , -(CH ₂ ) _p - Cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -ring Alkyl, -(CH2) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl are each independently optionally selected from hydrogen atoms, pendant oxy groups, halogens, One or more substituents in alkyl, haloalkyl, hydroxyalkyl, -OR ^cc , cyano, -NR ^dd R ^ee , nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;

R ^7a and R ^7b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group , aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group , cyano, -NR ^dd R ^ee , nitro, -OR ^cc , cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2 or 3;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 1, 2, 3, 4, 5 or 6;

r is 0, 1 or 2;

s is 0, 1, 2, 3, 4, or 5; and

t is 0, 1, 2, 3, 4 or 5.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II-2), or a tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

X, Ring A, Ring B, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , L, R ⁸ , R ^a , t, m and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II-3), or a tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , L, R ⁸ , R ⁹ , m and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II-4), or a tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , L, R ⁸ , m and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

X, Ring A, Ring C, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , L, R ^b , s, m and n are as defined in general formula (I).

、

、

、

、

和

；最佳地，環A 選自

、

和

。 In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; preferably, Ring A is selected from thiazolyl, dihydropyrrole pyrazolyl, 1,2,4-oxadiazolyl, dihydropyrrolothiazolyl and dihydropyrrolooxazolyl; more preferably, ring A is selected from

,

,

,

,

and

; Optimally, ring A is selected from

,

and

.

選自

、

、

和

，R⁸如通式(I)中所定義；較佳地，

選自

、

和

，R⁸如通式(I)中 所定義；更佳地，

為

，R⁸如通式(I)中所定義； 最佳地，

選自

、

和

。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

selected from

,

,

and

, R ⁸ is as defined in general formula (I); preferably,

selected from

,

and

, R ⁸ is as defined in general formula (I); more preferably,

for

, R ⁸ is as defined in general formula (I); Optimally,

selected from

,

and

.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ² is the same or different, and is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; preferably, R ² is hydrogen atom.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from C _1-6 alkyl, C _1-6 haloalkyl and -OR ^c , and R ^c is C _1-6 alkyl; preferably, R ³ is -OR ^c , and R ^c is C _1-6 alkyl; more preferably, R ³ is -OR ^c and R ^c is methyl.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or The compound represented by the general formula (II-5), or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt , wherein each R ⁴ is the same or different, and is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; preferably, R ⁴ is A hydrogen atom.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^X is an N atom or CRx, and Rx ^is a hydrogen atom.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^6a and R ^6b are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 hydroxyalkyl group, and -C(O)R ^c , and R ^c is a 3- to 8-membered cycloalkyl; preferably, R ^6a and R ^6b are different, and each independently is a hydrogen atom or -C(O)R ^c , and R ^c is a 3- to 6-membered cycloalkyl ; more preferably, R ^6a and R ^6b are different, and are each independently a hydrogen atom or -C(O)R ^c , and R ^c is cyclopropyl.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^7a and R ^7b are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl and C _1-6 Hydroxyalkyl; preferably, R ^7a and R ^7b are different and are each independently a hydrogen atom or CD ₃ .

In some preferred embodiments of the present disclosure, the general formula (I), the general formula (II-1), the general formula (II-2), the general formula (II-3) or the general formula (II-4) ^The compound shown, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is at each occurrence The same or different, and each independently is C _1-6 alkyl; preferably, R ⁸ is methyl.

In some preferred embodiments of the present disclosure, the general formula (I), the general formula (II-2), the general formula (II-3), the general formula (II-4) or the general formula (II-5) The compound shown, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is the same on each occurrence or different, and each independently is (CH2) _q or C(O), and q is 1.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II-2), or its tautomer, racemate, enantiomer, asymmetric enantiomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; Preferably, Ring B is piperazinyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II-2), or its tautomer, racemate, enantiomer, asymmetric An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^Ra is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II-3), or its tautomer, racemate, enantiomer, asymmetric An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is C _1-6 alkyl; preferably, R ⁹ is methyl.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; preferably, m is 1.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4) or A compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; preferably, n is 1.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X is an N atom or CR ^x , and R ^x is a hydrogen atom; ring A is selected from thiazolyl, dihydropyrrolopyrazolyl, 1,2,4-oxa oxadiazolyl, dihydropyrrolothiazolyl and dihydropyrrolooxazolyl; R ³ is selected from C _1-6 alkyl, C _1-6 haloalkyl and -OR ^c , and R ^c is C _1-6 alkyl; R ⁵ is a hydrogen atom; R ^6a and R ^6b are different, and each independently is a hydrogen atom or -C(O)R ^c , and R ^c is a 3- to 6-membered cycloalkyl; R ^7a and R ^7b are different , and each independently a hydrogen atom or CD ₃ ; R ⁸ is a C _1-6 alkyl group; m is 0; n is 0.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X is an N atom or CR ^x , and R ^x is a hydrogen atom; ring A is selected from thiazolyl, dihydropyrrolopyrazolyl, 1,2,4-oxa oxadiazolyl, dihydropyrrolothiazolyl and dihydropyrrolooxazolyl; R ² is a hydrogen atom; R ³ is selected from C _1-6 alkyl, C _1-6 haloalkyl and -OR ^c , and R ^c is C _1-6 alkyl; R ⁴ is a hydrogen atom; R ⁵ is a hydrogen atom; R ^6a and R ^6b are different and each independently a hydrogen atom or -C(O)R ^c , and R ^c is cyclopropyl R ^7a and R ^7b are different, and each independently is a hydrogen atom or CD ₃ ; R ⁸ is a C _1-6 alkyl group; m is 1;

選自

、

和

；R³為-OR^c，且 R^c為C_1-6烷基；R⁵為氫原子；R^6a和R^6b不同，且各自獨立地為氫原子或-C(O)R^c，且R^c為3至6員環烷基；R^7a和R^7b不同，且各自獨立地為氫原子或CD₃；R⁸為C_1-6烷基；n為0。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^X is an N atom or CRx, and Rx ^is a hydrogen atom;

selected from

,

and

; R ³ is -OR ^c , and R ^c is C _1-6 alkyl; R ⁵ is a hydrogen atom; R ^6a and R ^6b are different and are each independently a hydrogen atom or -C(O)R ^c , and R ^c is a 3- to 6-membered cycloalkyl; R ^7a and R ^7b are different, and are each independently a hydrogen atom or CD ₃ ; R ⁸ is a C _1-6 alkyl; n is 0.

選自

、

和

；R³為- OR^c，且R^c為C_1-6烷基；R⁵為氫原子；R^6a和R^6b不同，且各自獨立地為氫原子或-C(O)R^c，且R^c為環丙基；R^7a和R^7b不同，且各自獨立地為氫原子或CD₃；n為0。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^X is an N atom or CRx, and Rx ^is a hydrogen atom;

selected from

,

and

; R ³ is -OR ^c , and R ^c is C _1-6 alkyl; R ⁵ is a hydrogen atom; R ^6a and R ^6b are different and are each independently a hydrogen atom or -C(O)R ^c , and R ^c is cyclopropyl; R ^7a and R ^7b are different and each independently a hydrogen atom or CD ₃ ; n is 0.

Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure pertains to the compound represented by the general formula (IIa-1), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in the general formula (II-1).

Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to the compound represented by the general formula (IIa'-1), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in the general formula (II-1).

Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure pertains to compounds represented by general formula (IIa-2), or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or Its pharmaceutically acceptable salts:

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, Ring A, Ring B, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^a , t, m and n are as defined in general formula (II-2) .

Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure pertains to compounds represented by general formula (IIa-3), or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or Its pharmaceutically acceptable salts:

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, ring A, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ⁹ , m and n are as defined in general formula (II-3).

Typical compounds of the present disclosure include, but are not limited to:

Typical compounds of the present disclosure include, but are not limited to:

Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIa-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt is deprotected R ^w , to obtain the compound of general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in the general formula (II-1).

The compound represented by the general formula (II-1) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt comprises the following steps:

Compounds of general formula (IIa'-1) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts and ammoniums thereof The compound undergoes oxidation reaction to obtain the compound of general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable form Salt,

in,

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIa-2) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt is deprotected R ^w , to obtain the compound of general formula (II-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, Ring A, Ring B, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^a , t, m and n are as defined in general formula (II-2) .

Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II-3), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIa-3) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is deprotected R ^w , to obtain the compound of general formula (II-3) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, ring A, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ⁹ , m and n are as defined in general formula (II-3).

Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II-5), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof , or a method of a pharmaceutically acceptable salt thereof, comprising the steps of:

Compounds of general formula (IIa-5) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts and ammonium compounds Oxidation reaction occurs to obtain the compound of general formula (II-5) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

in,

X, Ring A, Ring C, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ^b , s, m and n are as defined in general formula (II-5).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising the general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-4), general formula Compounds of formula (II-5) and Table A or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof , and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to compounds of general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-5), and Table A or the compounds shown in Table A. Tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of TYK2 inhibition Use in medicine.

The present disclosure further relates to compounds of general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-5), and Table A or the compounds shown in Table A. Tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of therapeutic and/or Or use in a medicament to prevent a disease, disorder or condition mediated by TYK2.

The present disclosure further relates to compounds of general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-5), and Table A or the compounds shown in Table A. Tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of therapeutic and/or Or use in a medicament for preventing proliferative diseases, metabolic diseases, allergic diseases, inflammatory diseases or autoimmune diseases. The inflammatory disease or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis/psoriasis, silver Psoriatic arthritis, Crohn's disease, Sjögren's syndrome, systemic disease scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult Stills disease, juvenile idiopathic joint inflammation, gout, gouty arthritis, sepsis, septic shock, shigellosis, pancreatitis, glomerulonephritis, idiopathic nephritis, autoimmune hemolytic anemia, autoimmune neutropenia, Thrombocytopenia, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, pulmonary hemorrhagic nephritis (Goodpasture's) syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-related small vessel inflammation, pemphigus, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pneumonia, autoimmunity thyroiditis, autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy, preferably, the inflammatory disease or autoimmune disease is selected from rheumatoid arthritis, atopic dermatitis, psoriasis or Inflammatory bowel disease; the metabolic disease is diabetes (such as type I diabetes and insulin-dependent diabetes mellitus); the proliferative disease is cancer, preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer (such as colon and rectal cancer), lung cancer (such as non-small cell lung cancer and small cell lung cancer), stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer , kidney cancer, ovarian cancer, bladder cancer, liver cancer (such as hepatocellular carcinoma), fallopian tube tumors, peritoneal tumors, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.

The present disclosure further relates to a method of inhibiting TYK2, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II-2), formula (II-3), formula (II-4), Compounds of general formula (II-5) and Table A or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable compounds thereof A salt, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease, disorder or condition mediated by TYK2, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of Formula (I), Formula (II-2) , general formula (II-3), general formula (II-4), general formula (II-5) and the compounds shown in Table A or their tautomers, racemates, enantiomers, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a proliferative, metabolic, allergic, inflammatory or autoimmune disease comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the formula (I), the general formula (II-2), the general formula (II-3), the general formula (II-4), the general formula (II-5) and the compounds shown in Table A or their tautomers, external Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same. The inflammatory disease or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis/psoriasis, silver Psoriatic arthritis, Crohn's disease, Sjögren's syndrome, systemic disease scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult Still's disease, juvenile idiopathic arthritis, gout , gouty arthritis, sepsis, septic shock, shigellosis, pancreatitis, glomerulonephritis, spontaneous nephritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, pulmonary hemorrhagic nephritis syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-related Small vessel vasculitis, pemphigus, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pneumonia, autoimmunity thyroiditis, autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy, preferably, the inflammatory disease or autoimmune disease is selected from rheumatoid arthritis, atopic dermatitis, psoriasis or Inflammatory bowel disease; the metabolic disease is diabetes (such as type I diabetes and insulin-dependent diabetes); the proliferative disease is cancer, preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer (such as colon cancer) cancer and rectal cancer), lung cancer (such as non-small cell lung cancer and small cell lung cancer), stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer (eg hepatocellular carcinoma), fallopian tube tumors, peritoneal tumors, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.

The present disclosure further relates to a compound of general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-5) and Table A or Its tautomers, racemates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound of general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-5) and Table A or Its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting TYK2 .

The present disclosure further relates to a compound of general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-5) and Table A or Its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in therapy and /or preventing a disease, disorder or condition mediated by TYK2.

The present disclosure further relates to a compound of general formula (I), general formula (II-2), general formula (II-3), general formula (II-4), general formula (II-5) and Table A or Its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in therapy and/or Or prevent proliferative, metabolic, allergic, inflammatory or autoimmune diseases.

The inflammatory disease or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis/psoriasis, silver Psoriatic arthritis, Crohn's disease, Sjögren's syndrome, systemic disease scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult Still's disease, juvenile idiopathic arthritis, gout , gouty arthritis, sepsis, septic shock, shigellosis, pancreatitis, glomerulonephritis, idiopathic nephritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, platelets Atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, pulmonary hemorrhagic nephritic syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated small vessel vasculitis, pemphigus sores, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune Inflammatory eye disease and chronic demyelinating polyneuropathy; preferably, the inflammatory disease or autoimmune disease is selected from rheumatoid arthritis, atopic dermatitis, psoriasis and inflammatory bowel disease; the metabolic The sexual disease is diabetes (such as type I diabetes and insulin-dependent diabetes); the proliferative disease is cancer, preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer (such as colon cancer and rectal cancer), lung cancer (such as non-small cell lung cancer and small cell lung cancer), gastric cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer (such as hepatocellular carcinoma), Fallopian tube tumors, peritoneal tumors, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma, and myeloma.

The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure can also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compounds are preferably presented in unit doses or in such a manner that the patient can self-administer in a single dose. Unit doses of a compound or composition of the present disclosure can be expressed as tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstituted powders, or liquids. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients and the like. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.

Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain a one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the medical condition of the patient, the behavior, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment modality such as mode of treatment, daily dose of compound or pharmaceutically acceptable The type of salt can be verified according to traditional treatment protocols.

Glossary

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C _1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C _1-6 alkyl group). Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl , n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2 ,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4- Dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl ylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2- Methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. . Optimally lower alkyl groups of 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from H atom, D atom, halogen, alkyl, alkoxy, Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more of.

The term "(extended)alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or ₂₀ ) carbon atoms (ie C1-20(en)alkylene). The (extended) alkylene group is preferably a (extended) alkylene group having 1 to 12 carbon atoms (ie, a C _1-12 (extended) alkylene group), more preferably a (extended) alkylene group having 1 to 6 carbon atoms ) alkyl (ie C _1-6 (extend) alkylene). Non-limiting examples of alkylene groups include, but are not limited to: methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylidene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3 -Propylidene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The (extend) alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl , one or more of heteroaryl, cycloalkylthio, heterocycloalkylthio and pendant oxy.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, and preferably has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12) carbon atoms (ie C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent group is preferably selected from hydrogen atom, alkyl group, alkoxy group, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, hetero One or more of cyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to a molecule containing at least one carbon-carbon triple bond, wherein alkyl is as defined above, having 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11 or 12) carbon atoms (ie C _2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, hetero One or more of cyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy can be substituted or unsubstituted, when substituted, it can be substituted at any available point of attachment, the substituent is preferably selected from D atom, halogen, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered cycloalkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), most preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or poly-spirocycloalkyl groups (such as double-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups base. Better 3/5, 3/6, 4/4, 4/5, 4/6, 5-member/5-member, 5-member/6-member, 6-/6-member, 6-/4-member or 6-/5-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members sharing an adjacent pair of carbon atoms between the rings, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered /6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 5/7 6-member, 6-member/3-member, 6-member/4-member, 6-member/5-member, 6-member/6-member, 6-member/7-member, 7-member/5-member or 7-member/6-membered bicyclic fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl include:

)、四氫萘基(

)和 苯并環庚烷基(

)等；較佳

和

。 The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached at Rings taken together are cycloalkyl, non-limiting examples include indanyl (

), tetrahydronaphthyl (

) and benzocycloheptyl (

) etc.; preferably

and

.

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkanes of the radicals, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur optionally being oxidized (i.e. to form sulfite) or S), but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon. preferably have 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms (ie 3 to 12 membered heterocyclyl); more preferably have 3 to 8 ring atoms, wherein 1 to 3 (eg 1, 2 and 3) are heteroatoms (ie 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms of which 1 to 3 are heteroatoms (ie 3 to 8) 6-membered heterocyclyl); preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. 5 or 6 membered heterocycles) base). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl etc. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused ring heterocyclic groups and bridged ring heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members and a single atom sharing one atom (called a spiro atom) between the single rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the sulfur can be oxidized if desired (ie to form arsenic or arsenic), the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are divided into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiroheterocyclyl groups), preferably mono-spiroheterocyclyl groups and bis-spiroheterocyclyl groups ring base. Better 3/5, 3/6, 4/4, 4/5, 4/6, 5/5, 5/6 or 6/6 singles Spiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group with an adjacent pair of atoms shared between the rings, one or more rings may contain one or more double bonds, and one or more rings may contain one or more double bonds. The atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can be optionally oxidized (ie, to form selenium or susceptibility), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered /6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 5/7 member, 6-member/3-member, 6-member/4-member, 6-member/5-member, 6-member/6-member, 6-member/7-member, 7-member/5-member or 7-member/6-member bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms To be a heteroatom selected from nitrogen, oxygen, and sulfur, the sulfur may be optionally oxidized (ie, to form arsenite or arsenic), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocyclic, fused heterocyclic, and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the same as the parent structure The rings linked together are heterocyclyl, non-limiting examples of which include:

和

等。

and

Wait.

Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkanes of the radicals, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituents are preferably selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more of.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-10-membered (eg 5, 6, 7, 8, 9 or 10-membered), more preferably 5- or 6-membered heteroaryl, such as furyl, thienyl, pyridyl, pyrrolyl, N - Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from hydrogen, halogen, alkyl, alkoxy alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heterocyclyl one or more of the aryl groups.

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

The term "amine protecting group" refers to an easily removed group introduced on the amine group in order to keep the amine group unchanged when the other parts of the molecule are reacted. Non-limiting examples include: tertiary butyldimethylsilyl (TBS), (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tertiary butoxycarbonyl (Boc), benzyl Oxycarbonyl (Cbz), acetyl, benzyl, allyl and p-methoxybenzyl, etc. These groups are optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro.

The term "hydroxyl protecting group" refers to an easily detachable group introduced on a hydroxy group to block or protect the hydroxy group for reactions on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tertiary butyldimethylsilyl (TBS), tertiary Butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acetyl, acetyl, benzyl, p-nitrobenzyl and the like.

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to -OH.

The term "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "pendant oxygen" or "pendant oxy" refers to "=O".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, except replacing hydrogen with "deuterium" or "tritium", or replacing fluorine ^with18F -fluorine labeling ( ^18F isotope), or enriching ^with11C- , ^13C- , ^or14C- Compounds in which carbon ( ¹¹ C-, ¹³ C- or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C- or ¹⁴ C-isotopes) in place of carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.

One of ordinary skill in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.

Compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E ) isomers, (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, diastereomers isomers, (D )- and ( L )-isomers, tautomers, atropisomers, conformers, and mixtures thereof (eg, racemates, mixtures of diastereomers). Substituents in the compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, and (D )-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques and ( L )-isomers. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it can be combined with an appropriate Optically active acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to yield the pure isomers. In addition, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structures of the compounds described in this disclosure, the bond "

"Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond"

"can be"

"or"

", or both "

"and"

"Two configurations.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, ie as a single isomer or as a mixture of such tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamides, and the like. An example of a lactam-lactamine equilibrium is between A and B as shown below:

When referring to pyrazolyl, it should be understood to include either one of the following two structures or a mixture of two tautomers:

All tautomeric forms are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

"Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not occur. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. Those of ordinary skill in the art can determine possible or impossible substitutions without undue effort (either experimentally or theoretically). For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, together with other components such as a physiological/pharmaceutically acceptable carrier and excipient. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals, and have the desired biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in a case can be determined by those of ordinary knowledge in the art based on routine experiments.

The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of the crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

"Prodrug" means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and sometimes preferably within ±5%. As will be understood by one of ordinary skill in the art, when parameters are not critical, numbers are generally given for illustrative purposes only, rather than limitations.

Synthetic methods of compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

Option One

The compound represented by the general formula (II-1) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt comprises the following steps:

Compounds of general formula (IIa-1) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof under acidic conditions The protecting group R ^w is removed to obtain the compound of general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its medicinal salt,

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, Ring A, R ² to R ⁵ , R ^6a R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in the general formula (II-1).

Option II

The compound represented by the general formula (II-1) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt comprises the following steps:

Compounds of general formula (IIa'-1) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof in an oxidizing agent ( Preferably, in the presence of iodobenzene acetate), an oxidation reaction occurs with an ammonium compound (preferably ammonium acetate) to obtain a compound of general formula (II-1) or its tautomer, racemate, enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

in,

X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in the general formula (II-1).

third solution

The compound represented by the general formula (II-2) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt comprises the following steps:

Compounds of general formula (IIa-2) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof under acidic conditions The protecting group R ^w is removed to obtain the compound of general formula (II-2) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its medicinal salt,

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, Ring A, Ring B, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^a , t, m and n are as defined in general formula (II-2) .

Option 4

Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II-3), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIa-3) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof under acidic conditions The protecting group R ^w is removed to obtain the compound of general formula (II-3) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its medicinal salt,

in,

R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS);

X, ring A, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ⁹ , m and n are as defined in general formula (II-3).

Option five

The compound represented by the general formula (II-5) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt comprises the following steps:

Compounds of general formula (IIa-5) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof in an oxidizing agent (relative to Oxidation reaction with ammonium compounds (preferably ammonium acetate) in the presence of iodobenzene acetate to obtain the compound of general formula (II-5) or its tautomer, racemate, enantiomer, non- an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

in,

X, Ring A, Ring C, L, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ^b , s, m and n are as defined in general formula (II-5).

In the above-mentioned deprotection reaction, the acid in the acidic condition includes organic acid and inorganic acid, and the organic acid includes but is not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOTf, more Trifluoroacetic acid is preferred; the inorganic acid includes, but is not limited to, hydrogen chloride, a solution of hydrogen chloride in 1,4-dioxane, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, preferably a solution of hydrogen chloride in 1,4-dioxane.

The reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, acetic acid Ethyl ester, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and mixtures thereof.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 or Bruker AVANCE-500 nuclear magnetic instrument, and the solvent was deuterated dimethylsulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , the internal standard is tetramethylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.

Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

HPLC preparations were performed using Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for TLC separation and purification products is 0.4mm ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Accela ChemBio Inc. Darui Chemicals and other companies.

There is no special description in the examples, and the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.

Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the temperature of the reaction is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing agent system of the thin layer chromatography include: A : dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.

Example 1P

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-[4-( S -methanesulfonimidino)piperazine-1-carbonyl]thiazol-2-yl ]anilino]-N-( trideuteromethyl )pyridazine-3-carboxamide 1P

first step

4-(2-Bromothiazole-5-carbonyl)piperazine-1-carboxylate tert-butyl ester 1c

2-Bromothiazole-5-carboxylic acid 1a (5.00g, 24.03mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N , N' -dimethylformamide (30mL), followed by adding piperazine-1- 3-butyl carboxylate 1b (6.71g, 36.03mmol, Shanghai Shaoyuan Reagent Co., Ltd.), diisopropylethylamine (9.31g, 72.03mmol), 2-(7-azobenzotriazole)- Tetramethylurea hexafluorophosphate (8.48g, 36.04mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was reacted at room temperature for 20 hours, the reaction solution was poured into 50mL of water, extracted with ethyl acetate (50mL×3), and the ester phase was saturated with Washed with 50 mL of sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by column chromatography with eluent system B to obtain the title compound 1c (4.20 g), yield: 46%.

MS m/z (ESI): 378 [M+1] ⁺ .

second step

4-(2-(3-Amino-2-methoxyphenyl)thiazole-5-carbonyl)piperazine-1-carboxylate tert-butyl ester 1e

Compound 1c (2.00 g, 5.31 mmol) was dissolved in 1,4-dioxane (40 mL), water (4 mL), 2-methoxy-3-(4,4,5,5-tetramethyl) was added -1,3,2-dioxaborol-2-yl)aniline 1d (1.98 g, 7.95 mmol, synthesized according to the method disclosed in paragraph [00174] of WO2014074661A1 specification), [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (394mg, 0.53mmol), potassium carbonate (2.2g, 15.94mmol), replaced with nitrogen three times, heated to 100°C, stirred for 3 hours, poured into the reaction solution In water (50 mL), extracted with ethyl acetate (50 mL×2), the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography with eluent system B Purification gave the title compound 1e (1.20 g), yield: 54%.

MS m/z (ESI): 419.0 [M+1] ⁺ .

third step

4-(2-(3-((6-Chloro-3-(trideuteromethylaminocarboxy)pyridazin-4-yl)amino)-2-methoxy-phenyl)thiazole-5 -Carbonyl)piperazine-1-carboxylate tert-butyl ester 1g

Compound 1e (1.00 g, 2.38 mmol) was dissolved in dry tetrahydrofuran (20 mL), and 4,6-dichloro- N- (trideuteromethyl)pyridazine-3-carboxamide 1f (500 mg) was added under an ice-water bath. , 2.39mmol, synthesized according to the method disclosed in paragraphs [0426]-[0434] of the US20190152948A1 specification), bistrimethylsilylamide lithium (5.97mL, 5.97mmol, 1.0M tetrahydrofuran solution, Adamas reagent was added dropwise) Co., Ltd.), warmed to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and filtered with a column Purification by chromatography with eluent system B afforded the title compound 1 g (1.20 g), yield: 84%.

MS m/z (ESI): 591.0 [M+1] ⁺ .

the fourth step

4-(2-(3-((6-(Cyclopropanecarbamoyl)-3-(trideuteromethylaminocarbamoyl)pyridazin-4-yl)amino)-2-methoxy -Phenyl)thiazole-5-carbonyl)piperazine-1-carboxylate tert-butyl ester 1h

Compound 1 g (1.20 g, 2.03 mmol) was dissolved in 1,4-dioxane (10 mL), cyclopropanecarboxamide (861 mg, 10.11 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisdiphenyl was added Phosphine-9,9-dimethylxanthene (114 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium (184 mg, 0.20 mmol), cesium carbonate (2.64 g, 8.10 mmol), under nitrogen , microwave heating at 110 ℃ for 1 hour. The reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system A to obtain the title compound 1h (1.00 g), yield: 77%.

MS m/z (ESI): 640.3 [M+1] ⁺ .

the fifth step

6-(Cyclopropanecarboxamido)-4-[2-methoxy-3-[5-(piperazine-1-carbonyl)thiazol-2 - yl]anilino]-N-(trideuteromethyl) ) pyridazine-3-carboxamide 1i

Compound 1h (1.00 g, 1.56 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (10 mL, Yanfeng Technology Co., Ltd.), stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain the title compound 1i (900 mg), the product It was directly used in the next reaction without purification.

MS m/z (ESI): 540.1 [M+1] ⁺ .

Step 6

4-[3-[5-[4-[ N- [tert-butyl(dimethyl)silyl] -S -methyl-sulfoimido]piperazine-1-carbonyl]thiazole-2 -yl]-2-methoxy-anilino]-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-carboxamido 1k

Compound 1i (500 mg, 0.93 mmol) was dissolved in N , N -dimethylformamide (5 mL), and 1-( N- (tert-butyldimethylsilyl) -S -methylsulfonic acid was added Imido)-3-methyl-1 H -imidazole-3-trifluoromethanesulfonic acid onium salt 1j (590 mg, 1.39 mmol, synthesized according to the method disclosed in Chemistry, 2019, 25(28), 6928-6940) , diisopropylethylamine (358 mg, 2.77 mmol), heated to 80 °C, stirred for 5 hours, and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain the title compound 1k (350 mg), yield: 52%.

MS m/z (ESI): 731.2 [M+1] ⁺ .

Step 7

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-[4-( S -methanesulfonimidino)piperazine-1-carbonyl]thiazol-2-yl ]anilino]-N-( trideuteromethyl )pyridazine-3-carboxamide 1P

Compound 1k (330 mg, 0.45 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (10 mL, Yanfeng Technology Co., Ltd.), and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by liquid phase preparation (instrument model: Gilson 281 chromatography column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile Flow rate: 30 mL/min column temperature: room temperature) to obtain the title compound 1P (170 mg), yield: 61%.

MS m/z (ESI): 617.0 [M+1] ⁺ .

¹ H NMR (500MHz, DMSO- d ₆ )δ 11.36(s,1H), 10.98(s,1H), 9.26(s,1H), 8.27(s,1H), 8.12-8.14(m,1H), 8.08 (s,1H), 7.60-7.62(m,1H), 7.37-7.41(m,1H), 3.82(s,3H), 3.72-3.76(m,4H), 3.17-3.25(m,4H), 2.76 -2.78(m, 3H), 2.07-2.08(m, 1H), 0.79-0.84(m, 4H).

Example 2P

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydropyrrolo[3,4 - c ]pyrazol-2( 4H )-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 2P

first step

2-(2-Hydroxy-3-nitrophenyl)-4,6-dihydropyrrolo[3,4- c ]pyrazole-5( 2H )-carboxylic acid tert-butyl ester 2c

1-Bromo-2-methoxy-3-nitrobenzene 2a (500 mg, 2.15 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was combined with 4,6-dihydropyrrolo[3,4- c ]pyrazole- 5( 2H )-Third-butyl carboxylate 2b (676mg, 3.23mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in N , N -dimethylformamide (1mL), and cuprous iodide ( 82 mg, 0.43 mmol), (1 S ,2 S )-1,2-cyclohexanediamine (49 mg, 429 μmol), cesium carbonate (1.40 g, 4.29 mmol), microwave at 120° C. for 1 hour. After cooling, filter through celite, and after concentration, column chromatography was used to purify with eluent system C to obtain crude product 2c (746 mg). The product was directly used in the next reaction without further purification.

MS m/z (ESI): 347.0 [M+1] ⁺ .

second step

2-(2-Methoxy-3-nitrophenyl)-4,6-dihydropyrrolo[3,4- c ]pyrazole-5( 2H )-carboxylic acid tert-butyl ester 2d

The crude product 2c (746 mg, 2.15 mmol) was dissolved in N , N -dimethylformamide (4 mL), iodomethane (306 mg, 2.15 mmol), potassium carbonate (595 mg, 4.30 mmol) were added and heated at 60°C for 1 hour. After cooling, it was filtered, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography with eluent system B to give the title compound 2d (130 mg) in yield. : 17%.

MS m/z (ESI): 361.1 [M+1] ⁺ .

third step

2-(3-Amino-2-methoxyphenyl)-4,6-dihydropyrrolo[3,4- c ]pyrazole-5( 2H )-carboxylic acid tert-butyl ester 2e

Compound 2d (130 mg, 0.36 mmol) was dissolved in methanol (2 mL) and water (0.5 mL), ammonium chloride (58 mg, 1.08 mmol) and reduced iron powder (101 mg, 1.81 mmol) were added and heated at 80°C for 3 hours. After returning to room temperature, it was filtered through celite and concentrated to obtain the title compound 2e (119 mg). The product was directly used in the next step without purification.

MS m/z (ESI): 331.1 [M+1] ⁺ .

the fourth step

2-(3-((6-Chloro-3-(trideuteromethylaminocarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-4,6-dihydro Pyrrolo[3,4- c ]pyrazole-5( 2H )-carboxylate tert-butyl ester 2f

Compound 2e (125 mg, 0.38 mmol) and 1f (95 mg, 0.45 mmol) were dissolved in tetrahydrofuran (3 mL), and lithium bis(trimethylsilyl)amide (1.13 mL, 1.13 mmol, 1 M tetrahydrofuran) was added dropwise under an ice-water bath. solution, Anaiji Reagent Co., Ltd.), react at room temperature for 1 hour. Saturated ammonium chloride solution was added under ice-water bath for quenching, and extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and then subjected to column chromatography, and purified with eluent system B to obtain the title compound 2f (129 mg), yield: 68%.

MS m/z (ESI): 503.1 [M+1] ⁺ .

the fifth step

2-(3-((6-(6-Cyclopropanecarbamoyl)-3-(trideuteromethylaminocarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzene base)-4,6-dihydropyrrolo[3,4- c ]pyrazole-5( 2H )-carboxylic acid tert-butyl ester 2g

Compound 2f (129 mg, 0.26 mmol) was combined with cyclopropanecarboxamide (64 mg, 0.75 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), cesium carbonate (83 mg, 0.25 mmol), tris[dibenzylideneacetone]dipalladium (0) (23mg, 25μmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (15mg, 26μmol), 1,4-dioxane (0.5mL) mixed, under nitrogen protection under the microwave at 120°C for 30 minutes. After cooling, filter through a pad of celite, and after concentration, column chromatography was used to purify with eluent system B to obtain the title compound 2g (141 mg), yield: 99%.

MS m/z (ESI): 552.1 [M+1] ⁺ .

Step 6

6-(Cyclopropanecarboxamido)-4-((3-(5,6-dihydropyrrolo[3,4- c ]pyrazol-2( 4H )-yl)-2-methoxy Phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 2h

To compound 2g (141 mg, 0.26 mmol) was added 4M hydrogen chloride solution in 1,4-dioxane (3.0 mL), reacted at room temperature for 1 hour, concentrated to obtain the title compound 2h (115 mg), the product was directly put to the next step without purification .

MS m/z (ESI): 452.1 [M+1] ⁺ .

Step 7

4-((3-(5-( N- (tert-butyldimethylsilyl) -S -methylsulfonimido)-5,6-dihydropyrrolo[3,4- c ]pyrazol-2( 4H )-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-methyl Amide 2i

Compound 2h (115 mg, 0.25 mmol) was dissolved in N , N -dimethylformamide (2 mL), triethylamine (129 mg, 1.27 mmol) and compound 1j (139 mg, 0.51 mmol) were added and reacted at 50°C for 1 hour. After cooling, ethyl acetate (50 mL) was added to dilute, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography with eluent system B to obtain the title compound 2i (80 mg) in yield. : 49%.

MS m/z (ESI): 643.2 [M+1] ⁺ .

Step 8

6-(Cyclopropanecarbamido)-4-((2-2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydropyrrolo[3 ,4- c ]pyrazol-2( 4H )-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 2P

Compound 2i (80 mg, 0.12 mmol) was dissolved in methanol (1 mL), 4M hydrogen chloride solution in 1,4-dioxane (1.0 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After concentration, it was purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150mm; 5μm; C18 Mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min column temperature: room temperature) to obtain the title compound 2P (37mg ) with a yield of 56%.

MS m/z (ESI): 529.2 [M+1] ⁺ .

¹ H NMR (500MHz, DMSO- d ₆ )δ 11.36(s,1H), 11.02(s,1H), 9.17(s,1H), 8.18(s,1H), 8.02(s,1H), 7.46(ddd , J =13.7,8.1,1.6Hz,2H),7.31(t, J =8.1Hz,1H),4.55-4.37(m,4H),3.91(s,1H),3.50(s,3H),2.91( s, 3H), 2.14-2.03 (m, 1H), 0.90-0.73 (m, 4H).

Embodiment 3-P1, 3-P2

( R )-6-(cyclopropanecarbamido)-4-((2-2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro) Pyrrolo[3,4- c ]pyrazol-2( 4H )-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 3-P1

( S )-6-(Cyclopropanecarbamido)-4-((2-2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro Pyrrolo[3,4- c ]pyrazol-2( 4H )-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 3-P2

Compound 2P (33 mg, 0.062 mmol) was separated by a chiral preparative column (chromatographic column: CHIRALPAK IF 20*250 mm, 5 μm; mobile phase: A-n-hexane; B-ethanol (0.1% DEA), 80% B ratio elution , flow rate: 20mL/min, column temperature: room temperature) to obtain the title compound crude product. Subsequent preparative purification by liquid phase (instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5μm; C18 Mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min column temperature: room temperature) to obtain the title compounds 3-P1 (6 mg) and 3-P2 (6 mg) with a total yield of 36%.

Single configuration compound 3-P1 (shorter retention time)

MS m/z (ESI): 529.1 [M+1] ⁺ .

HPLC analysis: retention time 24 minutes, purity: 98%, ee value: 98% (chromatographic column: CHIRALPAK IF 20*250mm, 5μm; mobile phase: A-n-hexane; B-ethanol (0.1% DEA), 80% B ratio flushing, flow rate: 20mL/min, column temperature: room temperature).

¹ H NMR (500MHz, CD ₃ OD) δ 8.24(s, 1H), 7.95(s, 1H), 7.60-7.49(m, 1H), 7.49-7.41(m, 1H), 7.36-7.20(m, 1H) ),4.67-4.51(m,4H),3.53(s,3H),3.01(s,3H),2.00-1.89(m,1H),1.02-0.96(m,2H),0.96-0.87(m,2H ).

Single configuration compound 3-P2 (longer retention time)

MS m/z (ESI): 529.2 [M+1] ⁺ .

HPLC analysis: retention time 35 minutes, purity: 90%, ee value: 96% (chromatographic column: CHIRALPAK IF 20*250mm, 5μm; mobile phase: A-n-hexane; B-ethanol (0.1% DEA), 80% B ratio flushing, flow rate: 20mL/min, column temperature: room temperature).

¹ H NMR (500MHz, CD ₃ OD) δ 8.25(s, 1H), 7.90(s, 1H), 7.60(s, 1H), 7.48(dd, J=8.1, 1.5Hz, 1H), 7.42(dd, J=8.2,1.5Hz,1H),7.28(t,J=8.1Hz,1H),4.58-4.52(m,4H),3.54(s,3H),2.98(s,3H),1.89(tt,J =8.1,4.5Hz,1H),1.01(dt,J=6.6,3.4Hz,2H),0.91(dq,J=7.5,3.9Hz,2H).

Example 4P

6-(Cyclopropylcarbamoyl)-4-((3-(5-(((dimethyl(side oxygen)-λ ⁶ -sulfinyl)amino)methyl)-1,2, 4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 4P

The compound (Z)-6-(cyclopropanecarboxamido)-4-((3-( N' -hydroxyaminocarboxamido)-2 - methoxyphenyl)amino)-N-( Trideuteromethyl)pyridazine-3-carboxamide 4a (250mg, 0.62mol, synthesized according to the method disclosed in Example 6 of patent WO2020092196A1) was dissolved in N , N -dimethylformamide (5mL), followed by adding 2 -((Dimethyl(oxygen)-λ6-sulfinyl)amino)acetic acid 4b (187 mg, 1.2 mmol, synthesized according to the method disclosed in Tetrahedron, 2014, vol.70, 6613-6622), N , N - Diisopropylcarbodiimide (195 mg, 1.55 mmol, Adamas Reagent Co., Ltd.), stirred for 90 minutes, then heated to 80° C. to react for 4 hours. After cooling, the filtrate was concentrated under reduced pressure, and the reaction solution was concentrated under reduced pressure and purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM) Ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min Column temperature: room temperature) to give the title compound 4P (20 mg), yield: 6.2%.

MS m/z (ESI): 518.1 [M+1] ⁺ .

¹ H NMR (500MHz, MeOD) δ 8.22(s, 1H), 7.80(d, 1H), 7.70(d, 1H), 7.36(t, 1H), 4.60(s, 2H), 3.82(s, 3H) , 3.21(s, 6H), 2.00-1.86(m, 1H), 0.99-0.88(m, 4H).

Example 5P

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(2-( S -methylsulfoimido)thiazol-5-yl)phenyl)amino)- N- (trideuteromethyl)pyridazine-3-carboxamide 5P

first step

5-Bromo-2-(methylthio)thiazole 5b

Compound 2-(methylthio)thiazole 5a (0.85g, 6.48mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N , N -dimethylformamide (5mL), and N -butanediimide was added. (1.13 g, 7.75 mmol), stirred for 3 hours, poured the reaction solution into saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (50 mL×2), and washed the ester phase with saturated sodium chloride solution (50 mL), Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography with eluent system B to give the title compound 5b (0.85 g), yield: 62.4%.

MS m/z (ESI): 211.1 [M+1] ⁺ .

second step

2-Methoxy-3-(2-(methylthio)thiazol-5-yl)aniline 5c

Compound 5b (0.5 g, 2.38 mmol) was dissolved in 1,4-dioxane (5 mL), water (1 mL), 2-methoxy-3-(4,4,5,5-tetramethyl) was added -1,3,2-Dioxaborol-2-yl)aniline 1d (0.59 g, 2.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium (260 mg, 0.36 mmol), potassium carbonate (0.87 g, 5.9 mmol), replaced with nitrogen three times, heated to 100 ° C, stirred for 3 hours, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL ×2), the ester phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography with eluent system B to obtain the title compound 5c (0.4 g), yield: 67%.

MS m/z (ESI): 253.1 [M+1] ⁺ .

third step

6-Chloro-4-((2-methoxy-3-(2-(methylthio)thiazol-5-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3- Formamide 5d

Compound 5c (150 mg, 0.59 mmol) was dissolved in dry tetrahydrofuran (20 mL), compound 1f (124 mg, 0.59 mmol) was added under an ice-water bath, and lithium bistrimethylsilylamide (1.2 mL, 1.2 mmol, 1.0 mmol) was added dropwise. M tetrahydrofuran solution, Adamas Reagent Co., Ltd.), warmed to room temperature and stirred for 1 hour, poured the reaction solution into saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL×3), and the ester phase was saturated with saturated ammonium chloride solution (30 mL). Washed with sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by column chromatography with eluent system B to give the title compound 5d (160 mg), yield: 63.6%.

MS m/z (ESI): 425.3 [M+1] ⁺ .

the fourth step

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(2-(methylthio)thiazol-5-yl)phenyl)amino)-N-( trideuteromethyl ) yl)pyridazine-3-carboxamide 5e

Compound 5d (100 mg, 0.23 mmol) was dissolved in 1,4-dioxane (10 mL), and cyclopropanecarboxamide (100 mg, 1.17 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisdiphenyl group was added. Phosphine-9,9-dimethylxanthene (27mg, 46μmol), tris(dibenzylideneacetone)dipalladium (32mg, 35μmol), cesium carbonate (190mg, 0.58mmol), under nitrogen, microwave at 120°C React for 1 hour. The reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system A to obtain the title compound 5e (45 mg), yield: 40%.

MS m/z (ESI): 474.2 [M+1] ⁺ .

the fifth step

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(2-( S -methylsulfoimido)thiazol-5-yl)phenyl)amino)- N- (trideuteromethyl)pyridazine-3-carboxamide 5P

Compound 5e (30 mg, 63 μmol) was dissolved in absolute ethanol (3 mL), and iodobenzene acetate (61 mg, 0.18 mmol) and ammonium acetate (20 mg, 0.25 mmol) were added, stirred at room temperature for 5 hours, concentrated under reduced pressure, and the crude product was liquid-phase Preparative purification (instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5μm; C18 Mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min Column temperature: room temperature ) was purified to give the title compound 5P (5 mg), yield: 16%.

MS m/z (ESI): 505.2 [M+1] ⁺ .

¹ H NMR (500MHz, MeOH- d ₄ )δ 8.49(s,1H), 8.17(s,1H), 7.73(d,1H), 7.57(d,1H), 7.34(t,1H), 3.77(s , 3H), 3.36 (s, 3H), 1.35-1.33 (m, 1H), 1.00-0.87 (m, 4H).

Example 6P

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-((4-( S -methylsulfoimido)piperazin-1-yl)methyl )thiazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 6P

first step

1-( N- (tert-butyldimethylsilyl) -S -methylsulfoimido)piperazine 6b

The compound piperazine 6a (500mg, 5.8mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N , N -dimethylformamide (5mL), and N , N -diisopropylethylamine (2.25g, 17.4g) was added. mmol) and compound 1j (1.23g, 2.89mmol) were reacted at room temperature for 3 hours, the reaction solution was poured into water (30mL), extracted with ethyl acetate (50mL×2), and saturated sodium chloride solution (50mL) was used for the ester phase. ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 6b (400 mg), yield: 25%.

MS m/z (ESI): 278.2 [M+1] ⁺ .

second step

6-(Cyclopropanecarbamoyl)-4-((3-(5- carbodiazol -2-yl)-2-methoxyphenyl)amino)-N-(trideuteromethyl)pyridin oxazine-3-carboxamide 6d

The compound 6-(cyclopropanecarboxamido)-4-((3-(5-(hydroxymethyl)thiazol-2-yl)-2 - methoxyphenyl)amino)-N-(tris Deuteromethyl)pyridazine-3-carboxamide 6c (240mg, 0.52mmol, synthesized according to the method disclosed in Example 257 of patent WO2020092196A1) was dissolved in dichloromethane (5mL), and manganese dioxide (460mg, 5.2mmol) was added The reaction was warmed for 15 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6d (160 mg). The product was directly used in the next reaction without purification.

MS m/z (ESI): 456.1 [M+1] ⁺ .

third step

4-((3-(5-((4-( N- (tert-butyldimethylsilyl) -S -methylsulfonimido)piperazin-1-yl)methyl)thiazole -2-Methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-carboxamido 6e

Compound 6d (10 mg, 21 μmol) was dissolved in dichloroethane (20 mL), compound 6b (18 mg, 65 μmol), sodium triacetoxyborohydride (23 mg, 108 μmol, Adamas Reagent Co., Ltd.) were added, and the The reaction was warmed for 15 hours, the reaction solution was poured into saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (30 mL×3), the ester phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and reduced pressure. Concentration and purification by column chromatography with eluent system B afforded the title compound 6e (10 mg), yield: 64%.

MS m/z (ESI): 718.1 [M+1] ⁺ .

the fourth step

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-((4-( S -methylsulfoimido)piperazin-1-yl)methyl )thiazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 6P

Compound 6e (10 mg, 13 μmol) was dissolved in methanol (1 mL), a 4M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) was purified to obtain the title compound 6P (5 mg), yield: 60%.

MS m/z (ESI): 603.2 [M+1] ⁺ .

1H NMR (500MHz, MeOH- d ₄ )δ 8.16(s,1H), 8.03(d,1H), 7.76(s,1H), 7.56(d,1H), 7.32(t,1H), 4.58(s, 1H), 3.90(s, 2H), 3.81(s, 3H), 3.30(s, 2H), 3.24-3.21(m, 2H), 2.85(s, 2H), 2.65(t, 3H), 2.03(d , 1H), 1.33-1.30 (m, 1H), 0.99-0.94 (m, 4H).

Example 7P

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(2-(( N -methylsulfoimido)methyl)thiazol-5-yl)phenyl) Amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 7P

first step

3-(2-(1,3-dioxolan-2-yl)thiazol-5-yl)-2-methoxyaniline 7b

Compound 5-bromo-2-(1,3-dioxolan-2-yl)thiazole 7a (0.5 g, 2.11 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in 1,4-dioxane (5 mL ), water (1 mL), compound 1d (0.58 g, 2.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (230 mg, 0.32 mmol), potassium carbonate (0.73 g, 5.3 mmol), replaced with nitrogen three times, heated to 100 ° C, stirred for 3 hours, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL×2), the ester phase was saturated with sodium chloride The solution was washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography with eluent system B to give the title compound 7b (350 mg), yield: 59%.

MS m/z (ESI): 279.4 [M+1] ⁺ .

second step

4-((3-(2-(1,3-dioxolan-2-yl)thiazol-5-yl)-2-methoxyphenyl)amino)-6-chloro- N- (tris Deuteromethyl)pyridazine-3-carboxamide 7c

Compound 7b (200 mg, 0.72 mmol) was dissolved in dry tetrahydrofuran (20 mL), compound 1f (150 mg, 0.72 mmol) was added under an ice-water bath, and lithium bistrimethylsilylamide (1.43 mL, 1.43 mmol, 1.0 mmol) was added dropwise. M tetrahydrofuran solution, Adamas Reagent Co., Ltd.), warmed to room temperature and stirred for 1 hour, poured the reaction solution into saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL×3), and the ester phase was saturated with saturated ammonium chloride solution (30 mL). Washed with sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by column chromatography with eluent system B to give the title compound 7c (320 mg), yield: 99%.

MS m/z (ESI): 451.2 [M+1] ⁺ .

third step

4-((3-(2-(1,3-dioxolan-2-yl)thiazol-5-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide yl)-N-( trideuteromethyl )pyridazine-3-carboxamide 7d

Compound 7c (230 mg, 0.51 mmol) was dissolved in 1,4-dioxane (10 mL), and cyclopropanecarboxamide (260 mg, 3.0 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisdiphenyl group was added. Phosphine-9,9-dimethylxanthene (45mg, 76μmol), tris(dibenzylideneacetone)dipalladium (70mg, 76μmol), cesium carbonate (330mg, 1.0mmol), under nitrogen, microwave at 120°C React for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain the title compound 7d (150 mg), yield: 59%.

MS m/z (ESI): 500.2 [M+1] ⁺ .

the fourth step

6-(Cyclopropanecarbamoyl)-4-((3-(2- carbodiazol -5-yl)-2-methoxyphenyl)amino)-N-(trideuteromethyl)pyridin oxazine-3-carboxamide 7e

Compound 7d (80 mg, 0.16 mmol) was dissolved in tetrahydrofuran (2.5 mL), concentrated hydrochloric acid (0.5 mL, Shanghai Shaoyuan Reagent Co., Ltd.) was added, and the reaction was carried out at 70° C. for 3 hours. The reaction solution was added with saturated sodium bicarbonate solution, extracted with ethyl acetate, and concentrated under reduced pressure to obtain the title compound 7e (70 mg), yield: 96%.

MS m/z (ESI): 456.2 [M+1] ⁺ .

the fifth step

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(2-((methylamino)methyl)thiazol-5-yl)phenyl)amino) -N -(Trideuteromethyl)pyridazine-3-carboxamide 7f

Compound 7e (40 mg, 87 μmol) was dissolved in dichloroethane (20 mL), compound methylamine (0.5 mL, 0.5 mmol, 1 M solution in tetrahydrofuran), sodium triacetoxyborohydride (55 mg, 0.26 mmol, Adamas Reagent Co., Ltd.), stirred for 15 hours, poured the reaction solution into saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (30 mL×3), and washed the organic phase with saturated sodium chloride solution (30 mL), Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography with eluent system B to give the title compound 7f (30 mg), yield: 73%.

MS m/z (ESI): 471.3 [M+1] ⁺ .

Step 6

4-((3-(2-(( N '-(tert-butyldimethylsilyl) -N -methylsulfonimidoamido)methyl)thiazol-5-yl)-2 -Methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-carboxamido 7g

Compound 7f (30 mg, 64 μmol) was dissolved in N , N -dimethylformamide (5 mL), compound 1j (130 mg, 0.3 mmol), triethylamine (65 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 15 hours , the reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system A to obtain the title compound 7g (20mg), yield: 47%.

MS m/z (ESI): 662.3 [M+1] ⁺ .

Step 7

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(2-(( N -methylsulfoimido)methyl)thiazol-5-yl)phenyl) Amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 7P

Compound 7g (35 mg, 52 μmol) was dissolved in methanol (1 mL), a 4M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) was purified to obtain the title compound 7P (5 mg), yield: 52%.

MS m/z (ESI): 548.0 [M+1] ⁺ .

¹ H NMR (500MHz, MeOH- d ₄ )δ 8.23(d,1H), 7.61(d,1H), 7.58(t,1H), 7.53(d,1H), 7.33(t,1H), 4.62(s , 3H), 3.35(s, 2H), 3.03(d, 3H), 1.36(s, 3H), 1.33-1.28(m, 1H), 1.02-0.93(m, 4H).

Example 8P

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-(( N -methylsulfoimido)methyl)thiazol-2-yl)phenyl) Amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 8P

first step

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(5-((methylamino)methyl)thiazol-2-yl)phenyl)amino) -N -(Trideuteromethyl)pyridazine-3-carboxamide 8a

Compound 6d (200 mg, 0.44 mmol) was dissolved in dichloroethane (20 mL), compound methylamine (2.2 mL, 4.4 mmol, 2M in tetrahydrofuran), sodium triacetoxyborohydride (465 mg, 2.2 mmol) were added , Adamas Reagent Co., Ltd.), stirred for 15 hours, poured the reaction solution into saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (30 mL×3), and washed the ester phase with saturated sodium chloride solution (30 mL) , dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by column chromatography with eluent system B to obtain the title compound 8a (120 mg), yield: 58%.

MS m/z (ESI): 471.1 [M+1] ⁺ .

second step

4-((3-(5-(( N '-(tert-butyldimethylsilyl) -N -methylsulfoimidimido)methyl)thiazol-2-yl)-2 -Methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-carboxamido 8b

Compound 8a (150 mg, 0.32 mmol) was dissolved in N'N - dimethylformamide (5 mL), compound 1j (270 mg, 0.63 mmol) and triethylamine (160 mg, 1.6 mmol) were added, and the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system A to obtain the title compound 8b (80 mg), yield: 37.9%.

MS m/z (ESI): 662.3 [M+1] ⁺ .

third step

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-(( N -methylsulfoimido)methyl)thiazol-2-yl)phenyl) Amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 8P

Compound 8b (80 mg, 0.12 mmol) was dissolved in methanol (1 mL), a 4M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) to obtain the title compound 8P (12 mg), yield: 18%.

MS m/z (ESI): 548.2 [M+1] ⁺ .

¹ H NMR (500MHz, MeOH- d ₄ )δ 8.21(d,1H), 7.62(d,1H), 7.56(t,1H), 7.53(d,1H), 7.32(t,1H), 4.60(s , 3H), 3.37(s, 2H), 3.01(d, 3H), 1.38(s, 3H), 1.35-1.32(m, 1H), 1.01-0.89(m, 4H).

Example 9P

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-[[methyl-(methanesulfonimidino)amino]methyl]-1,2,4 -Oxadiazol -3-yl]anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide 9P

first step

N -[[3-[3-[[6-(Cyclopropanecarbamoyl)-3-(trideuteromethylaminocarbamoyl)pyridazin-4-yl]amino]-2-methoxy -Phenyl]-1,2,4-oxadiazol-5-yl]methyl] -N -methyl-carbamic acid tert-butyl ester 9b

Compound 4a (276 mg, 0.69 mmol) was dissolved in N , N -dimethylformamide (4 mL), and 2-[tert-butoxycarbonyl(methyl)amino]acetic acid 9a (260 mg, 1.37 mmol, 2-[tert-butoxycarbonyl(methyl)amino]acetic acid) was added. Shanghai Bide Reagent Co., Ltd.), then N , N' -diisopropylcarbodiimide (208 mg, 1.65 mmol, 255 μL, Shanghai Shaoyuan Reagent Co., Ltd.) was added, and the reaction mixture was stirred at room temperature for 90 minutes, followed by Tetrabutylammonium fluoride (3.2 mL, 3.2 mmol, 1M in tetrahydrofuran) was added, and the reaction mixture was stirred at room temperature for 4 hours, and then additional tetrabutylammonium fluoride (1.5 mL, 1.5 mmol, 1M in tetrahydrofuran) was added, and the maintenance was continued. Stir overnight at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, concentration, and purification by column chromatography with elution system A afforded the title compound 9b (164 mg) in 43% yield.

Ms m/z(ESI): 556.1[M+1] ⁺ .

second step

6-(Cyclopropanecarboxamido)-4-[2-methoxy-3-[5-(methylaminomethyl)-1,2,4-oxadiazol-3-yl]anilino] - N- (trideuteromethyl)pyridazine-3-carboxamide hydrochloride 9c

Compound 9b (164 mg, 0.30 mmol) was dissolved in dichloromethane (1.8 mL), 4M hydrogen chloride in 1,4-dioxane (0.59 mL) was added, and the reaction mixture was stirred at room temperature for two hours. Concentrated and spin-dried, and pumped to dryness to obtain the title compound 9c (145 mg). The product was directly used in the next reaction without purification.

Ms m/z(ESI): 456.1[M+1] ⁺ .

third step

4-[3-[5-[[[ N- [tert-butyldimethylsilyl] -S -methyl-sulfoimidino]-methyl-amino]methyl]-1, 2,4-Oxadiazol-3-yl]-2-methoxy-anilino]-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-carboxamido 9d

Compound 9c (145.2 mg, 0.3 mmol) was dissolved in acetonitrile (2.2 mL), triethylamine (149 mg, 1.48 mmol, 0.21 mL) was added, followed by compound 1j (225 mg, 0.53 mmol), and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, concentration and spin-drying gave the title compound 9d (75 mg), which was used in the next reaction without purification.

Ms m/z(ESI): 647.2[M+1] ⁺ .

the fourth step

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-[[methyl-(methanesulfonimidino)amino]methyl]-1,2,4 -Oxadiazol -3-yl]anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide 9P

Compound 9d (75 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), a 4M solution of hydrogen chloride in 1,4-dioxane (44 μL) was added, and the mixture was stirred at room temperature for 1 hour. Concentrated and spin-dried, the residue was dissolved in a small amount of methanol and sent to preparative chromatography for purification (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B - Acetonitrile flow rate: 30 mL/min column temperature: room temperature) to give the title compound 9P (12 mg) in 19% yield.

Ms m/z(ESI): 533.1[M+1] ⁺ .

¹ H NMR (500MHz, DMSO- d ₆ )δ 11.36(s,1H), 11.05(s,1H), 9.17(s,1H), 8.16(d,1H), 7.73(dd,1H), 7.70(dd ,1H),7.40(t,2H),4.81(s,2H),3.75(s,3H),2.96(s,3H),2.92(s,3H),2.06-2.11(m,1H),0.82- 0.86 (m, 4H).

Example 10P

6-(Cyclopropanecarboxamido)-4-((3-(5-((1-imino-1-oxo-N-thiomorpholino)methyl)-1,2,4-oxa oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(trideuteromethyl)pyridazine-3-carboxamide 10P

first step

6-(Cyclopropanecarboxamido)-4-[2-methoxy-3-[5-(N-thiomorpholinylmethyl)-1,2,4-oxadiazol-3-yl] Anilino]-N-( trideuteromethyl )pyridazine-3-carboxamide 10b

Compound 4a (280 mg, 0.696 mmol) and 2-N-thiomorpholinoacetic acid 10a (224 mg, 1.39 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were dissolved in N , N -dimethylformamide (5 mL), N , N' -diisopropylcarbodiimide (211 mg, 1.672 mmol) was added, and the reaction was carried out at room temperature for 90 minutes. Tetrabutylammonium fluoride (3.2 mL, 1 M, 3.2 mmol) was added, and the reaction was carried out at room temperature for 4 hours. Then tetrabutylammonium fluoride (3.2 mL, 1 M, 3.2 mmol) was added, and the reaction was carried out at room temperature overnight. 20 mL of water was added, extracted with ethyl acetate (20 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography, and purified with eluent system A to obtain crude product 10b (140 mg, 0.26 mmol), which was not used further. Purify and directly cast to the next step.

MS m/z (ESI): 528.1 [M+1] ⁺ .

second step

6-(Cyclopropanecarboxamido)-4-((3-(5-((1-imino-1-oxo-N-thiomorpholino)methyl)-1,2,4-oxa oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(trideuteromethyl)pyridazine-3-carboxamide 10P

Compound 10b (140 mg, 0.265 mmol) was dissolved in ethanol (5 mL), iodobenzene acetate (257 mg, 0.80 mmol) and ammonium acetate (82 mg, 1.06 mmol) were added, and the reaction was carried out at room temperature overnight. Model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5μm; C18 Mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min column temperature: room temperature) to obtain the title compound 10P (5 mg), yield: 3%.

MS m/z (ESI): 559.1 [M+1] ⁺ .

¹ H NMR (500MHz, DMSO- d ₆ )δ 11.36(s,1H), 11.05(s,1H), 9.17(s,1H), 8.16(s,1H), 7.73-7.69(m,2H), 7.41 -7.38(m, 1H), 5.34-5.32(m, 1H), 4.24(s, 2H), 3.67(s, 3H), 3.31-3.02(m, 8H), 0.87-0.82(m, 5H).

Example 11P

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(2-(4-( S -methylsulfonimidino)piperazine-1-carbonyl)thiazole-5 -yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 11P

first step

4-(5-Bromothiazole-2-carbonyl)piperazine-1-carboxylate tert-butyl ester 11b

Compound 5-bromothiazole-2-carboxylic acid 11a (300mg, 1.44mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N , N' -dimethylformamide (2mL), piperazine-1-carboxyl was added 3-butyl acid 1b (369mg, 1.44mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (407mg, 1.73mmol), diiso Propylethylamine (559 mg, 4.32 mmol) was reacted at room temperature overnight. Ethyl acetate (50 mL) was added to dilute, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography with eluent system B to obtain the title Compound 11b (330 mg), yield: 61%.

MS m/z (ESI): 275.9 [M-101+2] ⁺ .

second step

3-butyl 4-(5-(3-(3-amino-2-methoxyphenyl)thiazole-2-carbonyl)piperazine-1-carboxylate 11c

Compound 11b (330 mg, 0.88 mmol) and compound 1d (218 mg, 0.88 mmol) were dissolved in water (0.4 mL) and 1,4-dioxane (4 mL), [1,1'-bis(diphenyl) phosphino)ferrocene]palladium dichloride (64mg, 0.087mmol), anhydrous potassium carbonate (242mg, 1.75mmol), under nitrogen protection, react at 100°C for 3 hours. After cooling, it was diluted with ethyl acetate (100 mL), washed with water, and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to wash off-line system C to give the title compound 11c (317 mg) , yield: 86%.

MS m/z (ESI): 419.2 [M+1] ⁺ .

third step

4-(5-(3-((6-Chloro-3-((trideuteromethyl)aminocarboxy)pyridazin-4-yl)amino)-2-methoxyphenyl)thiazole- 2-Carbonylpiperazine-1-carboxylate tert-butyl ester 11d

Compound 1f (237 mg, 1.13 mmol) and compound 11c (317 mg, 0.76 mmol) were dissolved in tetrahydrofuran (3 mL), and lithium bistrimethylsilylamide (3.03 mL, 1.0 M solution in tetrahydrofuran, Adamer) was added under an ice-water bath. Si Reagent Co., Ltd.), react at room temperature for 1 hour. Saturated ammonium chloride solution was added to quench, extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to wash off-line system C to obtain the title compound 11d (278 mg), which was obtained as Rate: 62%.

MS m/z (ESI): 591.1 [M+1] ⁺ .

the fourth step

4-(5-(3-((6-(Cyclopropanecarboxamide)-3-((trideuteromethyl)aminocarbamoyl)pyridazin-4-yl)amino)-2-methoxy phenyl)thiazole-2-carbonyl)piperazine-1-acid tert-butyl ester 11e

Compound 11d (278 mg, 0.47 mmol) was combined with cyclopropanecarboxamide (120 mg, 1.41 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene ( 27mg, 0.047mmol), tris(dibenzylideneacetone)dipalladium (43mg, 0.047mmol), cesium carbonate (153mg, 0.47mmol), 1,4-dioxane (2mL) were mixed, under nitrogen protection, microwave heating (120°C) for 20 minutes. After cooling, dichloromethane (100 mL) was added to dilute, filtered, concentrated, and purified by column chromatography with eluent system A to obtain the title compound 11e (300 mg), yield: 99%.

MS m/z (ESI): 640.1 [M+1] ⁺ .

the fifth step

6-(Cyclopropanecarbonyl)-4-((2-methoxy-3-(2-(piperazine-1-carbonyl)thiazol-5-yl)phenyl)amino)-N-( trideuteromethyl ) base) pyridazine-3-carboxamide 11f

Compound 11e (300 mg, 0.47 mmol) was dissolved in hydrogen chloride in 1,4-dioxane (2 mL, 4M solution in 1,4-dioxane, Yanfeng Technology), stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain the title Compound 11f (253 mg), the product was directly used in the next reaction without purification.

MS m/z (ESI): 540.0 [M+1] ⁺ .

Step 6

4-[3-[5-[4-[ N- [tert-butyl(dimethyl)silyl] -S -methylsulfonimido]piperazine-1-carbonyl]thiazole-5- [methyl]-2-methoxy-anilino]-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-carboxamido 11g

Compound 11f (253 mg, 0.47 mmol) was dissolved in N , N' -dimethylformamide (3 mL), compound 1j (193 mg, 0.70 mmol), diisopropylethylamine (358 mg, 2.77 mmol) were added, React overnight at room temperature. After the reaction solution was concentrated under reduced pressure, it was purified by column chromatography with eluent system C to obtain 11 g (313 mg) of the title compound, yield: 91%.

MS m/z (ESI): 731.2 [M+1] ⁺ .

Step 7

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(2-(4-( S -methylsulfonimidino)piperazine-1-carbonyl)thiazole-5 -yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 11P

To compound 11 g (313 mg, 0.43 mmol) was added a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL), followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by liquid phase preparation (instrument model: waters2545 chromatography column: Sharpsil-T Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) to obtain the title compound 11P (67 mg), yield: 25%.

MS m/z (ESI): 617.2 [M+1] ⁺ .

¹ H NMR (500MHz, DMSO- d ₆ )δ 11.23(s,1H), 11.02(s,1H), 9.03(s,1H), 8.17(s,1H), 8.14(s,1H), 7.65(d , J =8.1Hz,1H),7.47(d, J =7.9Hz,1H),7.28(t, J =7.9Hz,1H),4.60-4.40(m,2H),3.85-3.72(m,2H) , 3.66(s, 3H), 3.57(s, 1H), 3.48-3.14(m, 4H), 2.74(s, 3H), 2.12-2.01(m, 1H), 0.87-0.71(m, 4H).

Example 12-P1, 12-P2

( R )-6-(Cyclopropanecarbamido)-4-((2-2-methoxy-3-(2-(4-( S -methylsulfonimidino)piperazine-1) -Carbonyl)thiazol-5-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 12-P1

( S )-6-(Cyclopropanecarbimido)-4-((2-2-methoxy-3-(2-(4-( S -methylsulfoimido)piperazine-1 -Carbonyl)thiazol-5-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 12-P2

Compound 11P (40 mg, 0.065 mmol) was separated by a chiral preparative column (chromatographic column: CHIRALPAK IF 20*250 mm, 5 μm; mobile phase: A-n-hexane; B-ethanol (0.1% DEA), 80% B ratio elution , flow rate: 20mL/min, column temperature: room temperature) to obtain the title compound crude product. Subsequent preparative purification by liquid phase (instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5μm; C18 Mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min column temperature: room temperature) to obtain the title compound (1.9 mg, 2.0 mg) with a total yield of 10%.

Single configuration compound (shorter retention time)

MS m/z (ESI): 617.1 [M+1] ⁺ .

HPLC analysis: retention time 75 minutes, purity: 99%, ee value: 98% (chromatographic column: CHIRALPAK IF 20*250mm, 5μm; mobile phase: A-n-hexane; B-ethanol (0.1% DEA), 80% B ratio flushing, flow rate: 20mL/min, column temperature: room temperature).

¹ H NMR (500MHz, CD ₃ OD) δ 8.34 (s, 1H), 8.21 (s, 1H), 7.61 (dd, J =7.9, 1.5Hz, 1H), 7.53 (dd, J =8.0, 1.5Hz, 1H), 7.31(t, J =8.0Hz, 1H), 4.57-4.44(m, 4H), 3.73(s, 3H), 3.43-3.37(m, 4H), 2.87(s, 3H), 1.96-1.88 (m, 1H), 1.00-0.94 (m, 2H), 0.94-0.87 (m, 2H).

Single configuration compound (longer retention time)

MS m/z (ESI): 617.1 [M+1] ⁺ .

HPLC analysis: retention time 93 minutes, purity: 99%, ee value: 96% (chromatographic column: CHIRALPAK IF 20*250mm, 5μm; mobile phase: A-n-hexane; B-ethanol (0.1% DEA), 80% B ratio flushing, flow rate: 20mL/min, column temperature: room temperature).

¹ H NMR (500MHz, CD ₃ OD) δ 8.31 (s, 1H), 8.22 (s, 1H), 7.58 (dd, J =7.9, 1.5Hz, 1H), 7.52 (dd, J =8.1, 1.5Hz, 1H), 7.30(t, J =7.9Hz, 1H), 4.45-4.42(m, 4H), 3.72(s, 3H), 3.42-3.35(m, 4H), 2.86(s, 3H), 1.95-1.87 (m, 1H), 1.04-0.96 (m, 2H), 0.95-0.87 (m, 2H).

Example 13P

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-(methanesulfonimidino)-4,6-dihydropyrrolo[3,4- d ]thiazole -2-yl]anilino]-N-( trideuteromethyl )pyridazine-3-carboxamide 13P

first step

2-(3-Amino-2-methoxy-phenyl)-4,6-dihydropyrrolo[3,4-dlthiazole-5-carboxylate tert-butyl ester 13b

2-Bromo- 4H -pyrrolo[3,4- d ]thiazole-5( 6H )-carboxylate tert-butyl ester 13a (500 mg, 1.64 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), compound 1d (612 mg, 2.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (121 mg, 0.16 mmol), potassium carbonate (678 mg) were added , 4.91 mmol), replaced with nitrogen three times, heated to 100 ° C, stirred for 2 hours, the reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system B to obtain the title compound 13b (500 mg), yield: 87% .

MS m/z (ESI): 348.0 [M+1] ⁺ .

second step

2-[3-[[6-Chloro-3-(trideuteromethylaminocarbamoyl)pyridazin-4-yl]amino]-2-methoxy-phenyl]-4,6-di Hydropyrrolo[3,4- d ]thiazole-5-carboxylate tert-butyl ester 13c

Compound 13b (250 mg, 0.72 mmol) was dissolved in dry tetrahydrofuran (5 mL), compound 1f (150 mg, 0.72 mmol) was added under ice-water bath, lithium bistrimethylsilylamide (1.79 mL, 1.79 mmol, 1.0 M tetrahydrofuran solution, Adamas Reagent Co., Ltd.), warmed to room temperature and stirred for 1 hour, poured the reaction solution into saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL×3), and the ester phase was saturated with saturated ammonium chloride solution (30 mL). Washed with sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by column chromatography with eluent system B to give the title compound 13c (250 mg), yield: 67%.

MS m/z (ESI): 520.0 [M+1] ⁺ .

third step

2-[3-[[6-(Cyclopropanecarboxamido)-3-(trideuteromethylamidocarboxyl)pyridazin-4-yl]amino]-2-methoxy-phenyl ]-4,6-Dihydropyrrolo[3,4- d ]thiazole-5-carboxylate tert-butyl ester 13d

Compound 13c (250 mg, 0.48 mmol) was dissolved in 1,4-dioxane (5 mL), and cyclopropanecarboxamide (204 mg, 2.39 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisdiphenyl group was added. Phosphine-9,9-dimethylxanthene (24 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.046 mmol), cesium carbonate (626 mg, 1.92 mmol), under nitrogen, microwave The reaction was carried out at 110°C for 1 hour. The reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system A to obtain the title compound 13d (90 mg), yield: 33%.

MS m/z (ESI): 569.1 [M+1] ⁺ .

the fourth step

6-(Cyclopropanecarboxamido)-4-[3-(5,6-dihydro- 4H -pyrrolo[3,4- d ]thiazol-2-yl)-2-methoxy-aniline yl]-N-( trideuteromethyl )pyridazine-3-carboxamide 13e

Compound 13d (80 mg, 0.14 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (4 mL, Yanfeng Technology Co., Ltd.), stirred at room temperature for 1 hour, and concentrated under reduced pressure to give the title compound 13e (80 mg). After purification, it was directly used in the next reaction.

MS m/z (ESI): 469.1 [M+1] ⁺ .

the fifth step

4-[3-[5-[ N- [tert-butyl(dimethyl)silyl] -S -methyl-sulfonimidyl]-4,6-dihydropyrrolo[3,4 - d ]Thiazol-2-yl]-2-methoxy-anilino]-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridazine - 3-carboxamido 13f

Compound 13e (72 mg, 0.15 mmol) was dissolved in N , N -dimethylamide (3 mL), compound 1j (83 mg, 0.30 mmol), triethylamine (78 mg, 0.77 mmol) were added, and the temperature was raised to 40°C, Stir overnight. The reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system A to obtain the title compound 13f (30 mg), yield: 30%.

MS m/z (ESI): 660.1 [M+1] ⁺ .

Step 6

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-(methanesulfonimidino)-4,6-dihydropyrrolo[3,4- d ]thiazole -2-yl]anilino]-N-( trideuteromethyl )pyridazine-3-carboxamide 13P

Compound 13f (30 mg, 0.045 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by liquid phase preparation (instrument model: waters2545 chromatography column: Sharpsil-T Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) to obtain the title compound 13P (5 mg), yield: 20%.

MS m/z (ESI): 546.0 [M+1] ⁺ .

¹ H NMR (500MHz, DMSO- d ₆ )δ 11.35(s,1H), 10.97(s,1H), 9.19(s,1H), 8.10(s,1H), 8.03-8.04(m,1H), 7.54 -7.56(m,1H),7.32-7.34(m,1H),4.54-4.68(m,4H),3.78(s,3H),2.91(s,3H),1.24(m,1H),0.79-0.83 (m, 4H).

Example 14P

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-(methylsulfoimido)-4,6-dihydropyrrolo[3,4- c ] Pyrazol -2-yl]anilino]-N-(trideuteromethyl)pyridine-3-carboxamide 14P

first step

2-[3-[[2-Chloro-5-(trideuteromethylaminocarbamoyl)-4-pyridyl]amino]-2-methoxy-phenyl]-4,6-dihydro Pyrrolo[3,4- c ]pyrazole-5-carboxylate tert-butyl ester 14b

4,6-Dichloro- N- (trideuteromethyl)nicotinamide 14a (60 mg, 0.30 mmol, synthesized according to the method disclosed in paragraph [00237] of the specification in patent WO2014074660A1) was dissolved in dry tetrahydrofuran (5 mL), Compound 2e (100 mg, 0.30 mmol) was added, lithium bistrimethylsilylamide (0.91 mL, 0.91 mmol, 1.0 M tetrahydrofuran solution, Adamas Reagent Co., Ltd.) was added dropwise, the temperature was raised to room temperature and stirred for 3 hours, The reaction solution was poured into saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL × 3), the ester phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and filtered with a column Purification by chromatography with eluent system B afforded the title compound 14b (130 mg), yield: 85%.

MS m/z (ESI): 503.2 [M+1] ⁺ .

second step

2-[3-[[2-(Cyclopropanecarbamoyl)-5-(trideuteromethylaminocarbamoyl)-4-pyridyl]amino]-2-methoxy-phenyl] -4,6-Dihydropyrrolo[3,4- c ]pyrazole-5-carboxylate tert-butyl ester 14c

Compound 14b (130 mg, 0.26 mmol) was dissolved in 1,4-dioxane (5 mL), cyclopropanecarboxamide (66 mg, 0.77 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), RuPhos Pd G3 (45 mg, 0.05 mmol) were added ), cesium carbonate (168 mg, 0.52 mmol), under nitrogen protection, microwave reaction at 110 °C for 1 hour. The reaction solution was concentrated under reduced pressure, purified by column chromatography with eluent system A to obtain the title compound 14c (80 mg), yield: 56%.

MS m/z (ESI): 551.0 [M+1] ⁺ .

third step

6-(Cyclopropanecarboxamido)-4-[3-(5,6-dihydro- 4H -pyrrolo[3,4- c ]pyrazol-2-yl)-2-methoxy- Anilino]-N-( trideuteromethyl )pyridine-3-carboxamide 14d

Compound 14c (60 mg, 0.11 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (2 mL, Yanfeng Technology Co., Ltd.), stirred at room temperature for 1 hour, and concentrated under reduced pressure to give the title compound 14d (50 mg). After purification, it was directly used in the next reaction.

MS m/z (ESI): 451.1 [M+1] ⁺ .

the fourth step

4-[3-[5-[ N- [tert-butyl(dimethyl)silyl]silyl] -S -methylsulfonimido]-4,6-dihydropyrrolo[3 ,4- c ]pyrazol-2-yl]-2-methoxy-anilino]-6-(cyclopropanecarboxamido)-N-(trideuteromethyl)pyridine - 3-carboxamido 14e

Compound 14d (50 mg, 0.11 mmol) was dissolved in N , N -dimethylformamide (3 mL), compound 1j (60 mg, 0.22 mmol), triethylamine (58 mg, 0.55 mmol) were added, and the mixture was stirred at room temperature overnight , add a small amount of water, and extract with ethyl acetate. Dry over anhydrous sodium sulfate and concentrate under reduced pressure to give the title compound 14e (20 mg). The crude product was used directly in the next step.

MS m/z (ESI): 642.2 [M+1] ⁺ .

the fifth step

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-(methylsulfoimido)-4,6-dihydropyrrolo[3,4- c ] Pyrazol -2-yl]anilino]-N-(trideuteromethyl)pyridine-3-carboxamide 14P

Compound 14e (20 mg, 0.031 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by liquid phase preparation (instrument model: waters2545 chromatography column: Sharpsil-T Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) to obtain the title compound 14P (5 mg), yield: 30%.

MS m/z (ESI): 526.3 [M-1] ⁻ .

¹ H NMR (500MHz, CDCl ₃ ) 10.50(s,1H), 8.30(s,1H), 8.17(s,1H), 8.11(s,1H), 7.92(s,1H), 7.49-7.51(m, 1H), 7.29-7.44(m, 1H), 6.17(s, 1H), 4.54-4.63(m, 4H), 3.61(s, 3H), 2.98(s, 3H), 1.53-1.62(m, 1H) , 1.09-1.11 (m, 2H), 0.91-0.93 (m, 2H).

Example 15P

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-((4-( S -methylsulfoimido)piperazin-1-yl)methyl )-1,2,4-oxadiazol-3-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 15P

first step

4-((3-(3-((6-(cyclopropanecarbamoyl)-3-((trideuteromethyl)aminocarbamoyl)pyridazin-4-yl)amino)-2- Methoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)piperazine-1-carboxylate tert-butyl ester 15b

Compound 4a (500mg, 1.24mmol) and 2-(4-tert-butoxycarbonylpiperazin-1-yl)acetic acid 15a (910mg, 3.72mmol, synthesized according to the synthesis method of Intermediate Example 23 in patent WO2013053983A1) Dissolve in N , N' -dimethylformamide (5mL), add N , N' -diisopropylcarbodiimide (313mg, 2.48mmol, Adamas Reagent Co., Ltd.), and react at room temperature for 1.5 hours . Tetrabutylammonium fluoride (6.21 mL, 6.21 mmol, 1M solution in tetrahydrofuran, Anagi Reagent Co., Ltd.) was added, and the reaction was carried out at room temperature overnight. After that, tetrabutylammonium fluoride (6.21 mL, 6.21 mmol, 1M solution in tetrahydrofuran, Anaiji Reagent Co., Ltd.) was added, and the reaction was carried out at room temperature overnight. Ammonium chloride solution was added under ice-water bath to quench, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography with elution system C to obtain the title compound 15b ( 296 mg), yield: 39%.

MS m/z (ESI): 611.2 [M+1] ⁺ .

second step

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(5-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-3-yl )phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 15c

To compound 15b (296 mg, 0.48 mmol) was added hydrochloric acid (2.49 mL, 9.98 mmol, 4M solution in 1,4-dioxane, Anagei Reagent Co., Ltd.), and reacted at room temperature for 1 hour. Concentrated directly to give the title compound 15c (240 mg), which was used in the next step without further purification.

MS m/z (ESI): 511.1 [M+1] ⁺ .

third step

4-((3-(5-((4-( N- (tert-butyldimethylsilyl) -S -methylsulfoimido)piperazin-1-yl)methyl)- 1,2,4-Oxadiazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-( trideuteromethyl )pyridazine-3 -formamide 15d

Compound 15c (240 mg, 0.48 mmol) was dissolved in N , N -dimethylformamide (3 mL), compound 1j (266 mg, 0.97 mmol), diisopropylethylamine (245 mg, 2.42 mmol,) were added , and reacted overnight at room temperature. Ethyl acetate (100 mL) was added to dilute, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography with eluent system C to obtain the title compound 15d (311 mg), yield: 91% .

MS m/z (ESI): 702.2 [M+1] ⁺ .

the fourth step

6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-((4-( S -methylsulfoimido)piperazin-1-yl)methyl )-1,2,4-oxadiazol-3-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 15P

Compound 15d (311 mg, 0.44 mmol) was dissolved in methanol (2 mL), 4M hydrogen chloride solution in 1,4-dioxane (2.0 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After concentration, it was purified by liquid phase preparation (instrument model: Gilson 281 chromatography column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min column temperature: room temperature) to obtain the title compound 15P ( 43 mg), yield: 16%.

MS m/z (ESI): 588.2 [M+1] ⁺ .

¹ H NMR (500MHz, DMSO- d ₆ )δ 11.34(s,1H), 11.03(s,1H), 9.15(s,1H), 8.30(s,1H), 8.13(s,1H), 7.73-7.69 (m, 1H), 7.68(d, J =8.0Hz, 1H), 7.38(t, J =7.9Hz, 1H), 3.73(s, 3H), 3.56(s, 1H), 3.21-3.06(m, 4H), 2.75-2.69 (m, 3H), 2.69-2.62 (m, 4H), 2.14-2.03 (m, 1H), 0.87-0.80 (m, 4H).

Example 16P

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-[[4-(methylsulfonimidino)]piperazin-1-yl]methyl]- 1,2,4-Oxadiazol-3-ylanilino]pyridine-3-carboxamide 16P

first step

6-Chloro-4-(3-cyano-2-methoxy-anilino)pyridine-3-carboxamide 16b

Compound 16a (650 mg, 3.40 mmol, synthesized according to the method disclosed in Journal of Medicinal Chemistry, 2017, 60, 9508-9530) was dissolved in dry tetrahydrofuran (20 mL), and 3-amino-2- Methoxy-benzonitrile (500 mg, 3.40 mmol) was added dropwise with lithium bistrimethylsilyl amide (10.13 mL, 10.130 mmol, 1.0 M solution in tetrahydrofuran, Adamas Reagent Co., Ltd.), the temperature was raised to room temperature and stirred After 1 hour, the reaction solution was neutralized with 1N dilute hydrochloric acid, and part of the tetrahydrofuran was spun off. The product was precipitated, filtered and washed with water to obtain the title compound 16b (700 mg). The product was used in the next reaction without further purification.

MS m/z (ESI): 303.2 [M+1] ⁺ .

second step

4-(3-Cyano-2-methoxy-anilino)-6-(cyclopropanecarboxamido)pyridine-3-carboxamido 16c

Compound 16b (300 mg, 0.99 mmol) was dissolved in 1,4-dioxane (5 mL), cyclopropanecarboxamide (253 mg, 2.97 mmol, Shanghai Shaoyuan Reagent Co., Ltd.), RuPhos Pd G3 (165 mg, 0.20 mmol) were added. mmol), cesium carbonate (975 mg, 2.97 mmol), under nitrogen protection, microwave heating at 120 °C for 1 hour. The reaction solution was filtered through celite, washed with dichloromethane, concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain the title compound 16c (100 mg), yield: 28%.

MS m/z (ESI): 352.0 [M+1] ⁺ .

third step

6-(Cyclopropanecarboxamido)-4-[3-[(Z) -N '-hydroxyaminocarboxamido]-2-methoxy-anilino]pyridine-3-carboxamido 16d

Compound 16c (100 mg, 0.284 μmol) hydroxylamine hydrochloride (202 mg, 2.91 mmol) was dissolved in ethanol (10 mL), potassium hydroxide (156 mg, 2.78 mmol) was added, and the mixture was heated at 80° C. for 24 hours. After cooling, concentration, adding dichloromethane and methanol to dissolve, filtering and concentrating to obtain the title compound 16d (60 mg), the product was directly used in the next reaction without further purification.

MS m/z (ESI): 385.1 [M+1] ⁺ .

the fourth step

4-[[3-[3-[[5-Aminocarbamoyl-2-(cyclopropanecarbamoyl)-4-pyridyl]amino]-2-methoxy-phenyl]-1 ,2,4-oxadiazol-5-yl]piperazine-1-carboxylate tert-butyl ester 16e

Compound 16d (80 mg, 0.21 mmol), compound 15a (102 mg, 0.42 mmol), N , N' -diisopropylcarbodiimide (52 mg, 0.41 mmol) were added to N , N -dimethylformamide , stirred at room temperature for 2 hours, added tetrabutylammonium fluoride (1M, 1.24 mL), and stirred at room temperature overnight. Quench by adding ammonium chloride solution. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography. Purification by column chromatography with eluent system A afforded the title compound 16e (30 mg), yield: 24%.

MS m/z (ESI): 593.2 [M+1] ⁺ .

the fifth step

6-(Cyclopropanecarboxamido)-4-[2-methoxy-3-[5-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-3-yl] Anilino]pyridine-3-carboxamide 16f

To compound 16e (30 mg, 0.051 mmol) was added 4M hydrogen chloride in 1,4-dioxane (1 mL, Yanfeng Technology), stirred at room temperature overnight, and rotated to dryness to give the title compound 16f (30 mg), the product was not purified, used directly in the next reaction.

MS m/z (ESI): 493.2 [M+1] ⁺ .

Step 6

4-[3-[5-[[4-[ N- [tert-butyl(dimethyl)silyl] -S -methyl-sulfoimido]piperazin-1-yl]methyl ]-1,2,4-oxadiazol-3-yl]-2-methoxy-anilino]-6-(cyclopropanecarboxamido)pyridine-3-carboxamide 16g

Compound 16f (30 mg, 0.061 mmol) was dissolved in N , N -dimethylformamide (3 mL), compound 1j (33 mg, 0.12 mmol), diisopropylethylamine (37 mg, 0.36 mmol) were added, The temperature was raised to 50°C, stirred for 5 hours, and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain 16 g (30 mg) of the title compound, yield: 72%.

MS m/z (ESI): 684.2 [M+1] ⁺ .

Step 7

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-[[4-(methylsulfonimidino)]piperazin-1-yl]methyl]- 1,2,4-Oxadiazol-3-ylanilino]pyridine-3-carboxamide 16P

Compound 16 g (20 mg, 0.029 mmol) was dissolved in a 4M hydrogen chloride solution (2 mL) in 1,4-dioxane, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by liquid phase preparation (instrument model: waters2545 chromatographic column: Sharpsil-T Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) to obtain the title compound 16P (3 mg), yield: 18%.

MS m/z (ESI): 570.9 [M+1] ⁺ .

¹ H NMR (500MHz, CDCl ₃ )δ 10.60(s, 1H), 8.38(s, 1H), 8.18(s, 1H), 8.13(s, 1H), 7.73-7.79(m, 1H), 7.70(d , J =8.0Hz,1H),7.33(t, J =7.9Hz,1H),4.02(s,2H),3.88(s,3H),3.36-3.37(m,4H),2.80-2.84(m, 7H), 2.23-2.26 (m, 1H), 0.87-0.80 (m, 4H).

Example 17P

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-(methylsulfoimido)-4,6-dihydropyrrolo[3,4- d ] Oxazol -2-yl]anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide 17P

first step

Methyl 2-methoxy-3-nitrobenzoate 17b

Methyl 2-hydroxy-3-nitrobenzoate 17a (100.00g, 507.24mmol , Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in N , N -dimethylformamide (800mL), potassium carbonate ( 140.21 g, 1.01 mmol), iodomethane (143.99 g, 1.01 mmol), heated at 60°C for 1 hour. After cooling, the reaction solution was poured into ice water, and the precipitated solid was filtered. The filter cake was dissolved in dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 17b (95.00 g), yield: 89%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.04 (dd, 8.0 Hz, 2.0 Hz, 1H), 7.92 (dd, 8.0 Hz, 1.6 Hz, 1H), 7.29 (t, 8.0 Hz, 1H), 4.01 (s) , 3H), 3.97(s, 3H).

second step

2-Methoxy-3-nitrobenzoic acid 17c

17b (0.60 g, 2.84 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), sodium hydroxide (1.14 g, 28.41 mmol) was added, and heated at 50°C for 2 hours. After cooling, the reaction solution was adjusted to pH (5~6) with 2M hydrochloric acid solution, and concentrated under reduced pressure to obtain the title compound 17c (1.00 g). The product was directly used in the next reaction without purification.

MS m/z (ESI): 196.1 [M-1] ⁻ .

third step

3-Hydroxy-4-(2-methoxy-3-nitrobenzylamino)pyrrolidine-1-carboxylate tert-butyl ester 17e

17c (1.90 g, 9.60 mmol) was dissolved in N , N' -dimethylformamide (20 mL), followed by the addition of 3-amino-4-hydroxypyrrolidine-1-carboxylate 3-butyl ester 17d ( 1.94g, 9.60mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.), triethylamine (2.62g, 25.92mmol), 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (4.05g , 14.46mmol, Shanghai Shaoyuan Reagent Co., Ltd.) reacted at room temperature for 20 hours, poured the reaction solution into 50mL of water, extracted with ethyl acetate (50mL×3), washed the ester phase with 50mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. , filtered, concentrated under reduced pressure, purified by column chromatography with eluent system B to give the title compound 17e (1.60 g), yield: 44%.

MS m/z (ESI): 404.5 [M+23] ⁺ .

3-(2-Methoxy-3-nitrobenzylamino)-4-oxypyrrolidine-1-carboxylate tert-butyl ester 17f

17e (3.08 g, 8.07 mmol) was dissolved in dichloromethane (80 mL), and (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodo-3 ( 1 H )-ketone (6.20 g, 14.53 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.), reacted at room temperature for 3 hours. The reaction solution was quenched by adding 50 mL of saturated sodium thiosulfate solution, extracted with dichloromethane (3×100 mL), the ester phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography. Purification with eluent system B gave the title compound 17f (0.76 g), yield: 25%.

MS m/z (ESI): 380.5 [M+1] ⁺ .

the fifth step

2-(2-Methoxy-3-nitrophenyl)-4,6-dihydro- 5H -pyrrolo[3,4- d ]oxazole-5-carboxylic acid tert-butyl ester 17g

Triphenylphosphine (1.57 g, 3.00 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in dichloromethane (30 mL), and hexachloroethane (1.18 g, 5.00 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was added. and triethylamine (1.20 g, 6.00 mmol) at room temperature for 30 minutes. A solution of 17f (0.76 g, 2.00 mmol) in dichloromethane (5 mL) was added, reacted at room temperature for 36 hours, concentrated under reduced pressure, and purified by column chromatography with eluent system B to obtain the title compound 17 g (0.53 g), yielding Rate: 70%.

MS m/z (ESI): 362.5 [M+1] ⁺ .

Step 6

2-(3-Amino-2-methoxyphenyl) -4H -pyrrolo[3,4- d ]oxazole-5( 6H )-carboxylate tert-butyl ester 17h

Compound 17g (500mg, 1.38mmol) was dissolved in methanol (10mL) and water (10mL), ammonium chloride (740mg, 13.84mmol) and reduced iron powder (386mg, 6.92mmol) were added and heated at 80°C for 3 hours. After returning to room temperature, it was filtered through celite, concentrated, and purified by column chromatography with eluent system B to obtain the title compound 17h (360 mg), yield: 79%.

MS m/z (ESI): 332.0 [M+1] ⁺ .

Step 7

2-[3-[[6-Chloro-3-(trideuteromethylaminocarbamoyl)pyridazin-4-yl]amino]-2-methoxy-phenyl]-4,6-di Hydropyrrolo[3,4- d ]oxazole-5-carboxylate tert-butyl ester 17i

Compound 17h (150 mg, 0.45 mmol) and 1f (104 mg, 0.50 mmol) were added dropwise in an ice-water bath with lithium bis(trimethylsilyl)amide (2.26 mL, 2.26 mmol, 1M solution in tetrahydrofuran, Anegis reagent) Co., Ltd.), react at room temperature for 1 hour. Saturated ammonium chloride solution was added in an ice-water bath for quenching, extracted with dichloromethane (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography, and purified with eluent system B to obtain the title compound 17i (180 mg), yield: 78%.

MS m/z (ESI): 504.0 [M+1] ⁺ .

Step 8

2-[3-[[6-(Cyclopropanecarboxamido)-3-(trideuteromethylamidocarboxyl)pyridazin-4-yl]amino]-2-methoxy-phenyl ]-4,6-Dihydropyrrolo[3,4- d ]oxazole-5-carboxylic acid tert-butyl ester 17j

Compound 17i (210 mg, 0.42 mmol) was combined with cyclopropanecarboxamide (71 mg, 0.83 mmol), cesium carbonate (339 mg, 1.04 mmol), tris[dibenzylideneacetone]dipalladium(0) (38 mg, 41 μmol), 4,5-Bisdiphenylphosphine-9,9-dimethylxanthene (24 mg, 41 μmol) and 1,4-dioxane (5 mL) were mixed, and the tube was sealed and heated at 130° C. for 5 hours under nitrogen protection. After cooling, filter through a pad of celite, and after concentration, column chromatography was used to purify with eluent system B to obtain the title compound 17j (170 mg), yield: 74%.

MS m/z (ESI): 552.9 [M+1] ⁺ .

Step 9

6-(Cyclopropanecarboxamido)-4-[3-(5,6-dihydro- 4H -pyrrolo[3,4- d ]oxazol-2-yl)-2-methoxy- Anilino]-N-( trideuteromethyl )pyridazine-3-carboxamide 17k

4M hydrogen chloride in 1,4-dioxane solution (1 mL) was added to compound 17j (90 mg, 0.16 mmol), reacted at room temperature for 1 hour, and concentrated to obtain the title compound 17k (73 mg). The product was directly used in the next step without purification.

MS m/z (ESI): 452.9 [M+1] ⁺ .

Step 10

4-[3-[5-[ N- [tert-butyl(dimethyl)silyl] -S -methyl-sulfonimidyl]-4,6-dihydropyrrolo[3,4 - d ] oxazol-2-yl]-2-methoxy-anilino]-6-(cyclopropanecarboxamido)-N-( trideuteromethyl )pyridazine - 3-carboxamido 17l

Compound 17k (50 mg, 0.11 mmol) was dissolved in N , N -dimethylformamide (1 mL), triethylamine (33 mg, 0.33 mmol), compound 1j (61 mg, 0.22 mmol) were added, and the reaction was carried out at 50°C for 1 hour. After cooling, ethyl acetate (30 mL) was added to dilute, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography with eluent system B to obtain the title compound 17l (35 mg), yield : 49%.

MS m/z (ESI): 644.1 [M+1] ⁺ .

Step 11

6-(Cyclopropanecarbamido)-4-[2-methoxy-3-[5-(methylsulfoimido)-4,6-dihydropyrrolo[3,4- d ] Oxazol -2-yl]anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide 17P

Compound 17l (32 mg, 0.05 mmol) was dissolved in methanol (1 mL), 4M hydrogen chloride solution in 1,4-dioxane (1.0 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After concentration, it was purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150mm; 5μm; C18 mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min column temperature: room temperature) to obtain the title compound 17P (15mg ) with a yield of 57%.

MS m/z (ESI): 530.1. [M+1] ⁺ .

¹ H NMR (500MHz, CDCl ₃ )δ 11.07(s,1H), 9.16(s,1H), 8.26(s,1H), 8.12(s,1H), 7.77-7.79(m,1H), 7.60-7.62 (m,1H),7.29-7.35(m,1H),4.45-4.66(m,4H),3.90(s,3H),2.99(s,3H),2.55(s,1H),1.26-1.28(m , 1H), 0.92-1.14 (m, 4H).

Example 18-P1, 18-P2

( R )-6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro- 4 H -pyrrolo[3,4-d]oxazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carbamide 18-P1

( S )-6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro- 4 H -pyrrolo[3,4-d]oxazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carbamide 18-P2

first step

( S )-4-((3-(5-( N- (tert-butyldimethylsilyl) -S -methylsulfonimidoyl)-5,6-dihydro- 4H -Pyrrolo[3,4-d]oxazol-2-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-( trideuteromethyl )pyridin oxazine-3-carboxamide 17l-P1

( R )-4-((3-(5-( N- (tert-butyldimethylsilyl) -S -methylsulfonimidyl)-5,6-dihydro- 4H -Pyrrolo[3,4-d]oxazol-2-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-( trideuteromethyl )pyridin oxazine-3-carboxamide 17l-P2

Compound 17l (1970 mg, 3.06 mmol) was separated by a chiral preparative column (chromatographic column: CHIRALCEL OZ 5.0 cm ID*25 cm L, 10 μm; mobile phase: A-methanol; B-acetonitrile, 15% B ratio elution, flow rate: 66 mL/min, column temperature: 38 °C) to obtain the title compound (810 mg, 900 mg) in a total yield of 87%.

Single configuration compound (shorter retention time)

MS m/z (ESI): 644.1 [M+1] ⁺ .

HPLC analysis: retention time 4.652 minutes, purity: 99%, ee value: 99.55% (chromatographic column: CHIRALCEL OZ-H (OZH0CD-OD010) 0.46cm I.D.*15cm L; mobile phase: A-methanol 100% A proportional flushing extraction, flow rate: 1.0 mL/min, column temperature: 35 °C).

Single configuration compound (longer retention time)

MS m/z (ESI): 644.1 [M+1] ⁺ .

HPLC analysis: retention time 6.407 minutes, purity: 99%, ee value: 99.54% (chromatographic column: CHIRALCEL OZ-H (OZH0CD-OD010) 0.46cm I.D.*15cm L; mobile phase: A-methanol 100% A proportional flushing extraction, flow rate: 1.0 mL/min, column temperature: 35 °C).

second step

( R )-6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro- 4H -pyrrolo[3,4-d]oxazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 18-P1 or ( S )- 6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro- 4H -pyrrole [3,4-d]oxazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 18-P2

The compound corresponding to the shorter retention time in 171-P1 or 171-P2 (800 mg, 1.24 mmol) was dissolved in a mixed solvent of dichloromethane (4 mL) and methanol (4 mL), and 4M hydrogen chloride in 1,4-dioxane was added. The solution (12 mL) was stirred and reacted at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150 mm; 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) to give the title compound (520 mg) in 79% yield.

MS m/z (ESI): 530.1 [M+1] ⁺ .

¹ H NMR (500MHz, CDCl ₃ )δ 11.07(s,1H), 9.16(s,1H), 8.26(s,1H), 8.12(s,1H), 7.77-7.79(m,1H), 7.60-7.62 (m,1H),7.29-7.35(m,1H),4.45-4.66(m,4H),3.90(s,3H),2.99(s,3H),2.55(s,1H),1.26-1.28(m , 1H), 0.92-1.14 (m, 4H).

( R )-6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro- 4H -pyrrolo[3,4-d]oxazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 18-P1 or ( S )- 6-(Cyclopropanecarbamido)-4-((2-methoxy-3-(5-( S -methylsulfonimidino)-5,6-dihydro- 4H -pyrrole [3,4-d]oxazol-2-yl)phenyl)amino)-N-( trideuteromethyl )pyridazine-3-carboxamide 18-P2

The compound corresponding to the longer retention time in 171-P1 or 171-P2 (900 mg, 1.40 mmol) was dissolved in a mixed solvent of dichloromethane (4 mL) and methanol (4 mL), and 4M hydrogen chloride in 1,4-dioxane was added. The solution (12 mL) was stirred and reacted at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by liquid phase preparation (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30*150 mm; 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile flow rate: 30 mL/min column temperature: room temperature) to give the title compound (500 mg) in 68% yield.

MS m/z (ESI): 530.1 [M+1] ⁺ .

¹ H NMR (500MHz, CDCl ₃ )δ 11.07(s,1H), 9.16(s,1H), 8.26(s,1H), 8.12(s,1H), 7.77-7.79(m,1H), 7.60-7.62 (m,1H),7.29-7.35(m,1H),4.45-4.66(m,4H),3.90(s,3H),2.99(s,3H),2.55(s,1H),1.26-1.28(m , 1H), 0.92-1.14 (m, 4H).

Biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present disclosure.

Test Example 1: KdELECT Competitive Binding Assay of Compounds of the Disclosure

The KdELECT competition binding assay was performed by CRO, Eurofins DiscoverX Corporation according to established standard protocols (DiscoverX, San Diego, CA). Briefly, a kinase-tagged T7 phage strain was prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log phase and infected with T7 phage and incubated at 32°C with shaking until lysed. Lysates were centrifuged and filtered to remove cellular debris. The remaining kinases were produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to generate affinity resins for kinase assays. Ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific binding. Binding reactions were assembled by binding kinase, ligand affinity beads and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were made as 111x-stock solutions in 100% DMSO. Kds were determined using compound 3-fold dilutions with three DMSO control spots for a total of 11 doses. All compounds used for Kd measurements were dispensed into 100% DMSO by acoustic transfer (non-contact dispensing). Compounds were then diluted directly into the assay to give a final concentration of 0.9% DMSO. All reactions were performed on polypropylene 384-well plates. Each has a final volume of 0.02 mL. The assay plate was incubated for 1 hour at room temperature with shaking, and the affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. The kinase concentration in the eluate was measured by quantitative PCR.

Compound treatment: Prepare dilutions of each test compound in 100% DMSO at 100% final test concentration, 3-fold dilution for a total of 11 doses, then dilute to 1-fold in the assay (final DMSO concentration = 1%) . Most Kds were determined using the highest compound concentration = 30,000 nM. If the initial Kd was determined to be < 0.5 nM (the lowest concentration tested), the measurement was repeated with serial dilutions starting from the lower highest concentration. The reported Kd value was 40,000 nM, indicating that Kd was determined to be >30,000 nM.

Table 1 KdELECT data of the disclosed compounds

Conclusion: The disclosed compounds have significant inhibitory effects on TYK2 JH2 pseudokinase and ligand binding, thus revealing the high affinity of the compounds for TYK2 JH2.

Test Example 2: Test of compounds of the present disclosure on IL-23_Kit225 T cells

Kit225 cells (licensed by Prof. Toshiyuki Hori, Ritsumeikan University, Japan) were seeded in 384-well plates at a density of ¹ x 105 cells/well and placed in 4 μL of Hank's Balanced Salt Solution (HBSS, Gibco) and incubated at 2°C. Incubate for 2 hours. Humidified 5% _CO2 cell incubator at 37 °C. Cells were treated with serial dilutions of compounds for 1 hour and stimulated with human recombinant IL-23 (R&D Systems) for 20 minutes. The treated cells were then lysed and the levels of cellular phosphorylated STAT3 were measured by AlphaLISA (PerkinElmer) according to the manufacturer's instructions. Inhibition data were calculated by comparing 0% inhibition with vehicle control wells and 100% inhibition with unstimulated control wells. Dose-response curves were then generated to determine the concentration required to inhibit 50% of the cellular response ( _IC50 ) by nonlinear regression analysis using GraphPad Prism.

Table 2 Inhibitory activity of the disclosed compounds on IL-23_Kit225 T cells

Conclusion: The disclosed compounds have inhibitory effects on TYK2-mediated, IL23-induced STAT3 phosphorylation in the human Kit225 T cell line.

Test Example 3: Test of the disclosed compounds on IFNα_Kit225 T cells

Kit225 cells were seeded in 4 μL of HBSS in a 384-well plate at a density of 0.5×10 ⁵ cells/well and incubated for 2 h at 37 °C in a 5% CO ₂ cell incubator. Cells were treated with serial dilutions of compounds for 1 hour and stimulated with human recombinant IFNα (Biolegend) for 20 minutes. The treated cells were then lysed and the levels of cellular phosphorylated STAT1 were measured by AlphaLISA (PerkinElmer) according to the manufacturer's instructions. Inhibition data were calculated by comparing 0% inhibition with vehicle control wells and 100% inhibition with unstimulated control wells. Dose-response curves were then generated to determine the concentration required to inhibit 50% of the cellular response ( _IC50 ) by nonlinear regression analysis using GraphPad Prism.

Table 3 Inhibitory activity of the disclosed compounds on IFNα_Kit225 T cells

Conclusion: The disclosed compounds have inhibitory effects on TYK2-mediated, IFNα-induced STAT1 phosphorylation in the human Kit225 T cell line.

Test Example 4: Pharmacokinetic evaluation of the compounds of the present disclosure in C57 mice

1. Abstract

Taking C57 mice as the test animals, the LC/MS/MS method was used to determine the drug concentrations in the plasma of C57 mice after intragastric administration of the test compounds at different times. To study the pharmacokinetic behavior of the disclosed compounds in C57 mice, and to evaluate their pharmacokinetic characteristics.

2. Test plan

2.1 Test Drugs

Compound 3-P1 .

2.2 Experimental animals

Dosage of 15 mg/kg: 9 C57 mice, female, provided by Weitong Lihua Laboratory Animal Co., Ltd.

Dosage 50 mg/kg: 18 C57 mice, female, randomly divided into 2 groups, purchased from Zhejiang Weitong Lihua Laboratory Animal Co., Ltd., animal production license number: SCXK (Zhe) 2019-0001.

2.3 Drug preparation

Dosage 15mg/kg: Weigh a certain amount of medicine, add 5% EtOH, 5% TPGS and 90% PEG300, and configure it into a white opaque oily liquid.

Dosage 50mg/kg: Weigh a certain amount of medicine, add 5% EtOH, 5% TPGS and 90% PEG300 to prepare a yellowish transparent viscous solution.

2.4 Administration

No fasting was required on the night before administration, and the patients were administered by gavage.

3. Operation

In the intragastric administration group, 0.1 mL of blood was collected at 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, 11.0h, and 24.0h after administration, placed in an EDTA-K2 anticoagulation test tube, and centrifuged at 10000rpm. 1min (4°C), the plasma was separated within 1h, and stored at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions.

Determination of the content of the test compound in the plasma of C57 mice after intragastric administration of different concentrations of drugs: take 25 μL of C57 mouse plasma at each time after administration, add 50 μL of internal standard solution (internal standard solution with a dose of 15 mg/kg) : Camptothecin 100ng/mL; Internal standard solution at a dose of 50mg/kg: Tolbutamide 100ng/mL), acetonitrile 175μL, vortexed for 5 minutes, centrifuged for 10 minutes (4000 rpm), and the plasma sample was taken 1 μL of the supernatant was subjected to LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 4 Pharmacokinetic parameters of the disclosed compounds in C57 mice

Conclusion: The disclosed compound 3-P1 has good drug metabolism and absorption in C57 mice, and has the advantages of pharmacokinetics.

Test Example 5: Pharmacokinetic evaluation of the compounds of the present disclosure in SD rats

1. Abstract

Using SD rats as test animals, LC/MS/MS method was used to determine the drug concentration in the plasma of SD rats at different times after intragastric administration of the test compounds. To study the pharmacokinetic behavior of the disclosed compounds in SD rats, and to evaluate their pharmacokinetic characteristics.

2. Test plan

2.1 Test Drugs

Compound 3-P1 .

2.2 Experimental animals

Four SD rats, half male and half male, were equally divided into 2 groups, with 2 rats in each group, purchased from Zhejiang Weitong Lihua Experimental Animal Co., Ltd., production license number: SCXK (Zhe) 2019-0001.

2.3 Drug preparation

A certain amount of medicine was weighed, 5% DMSO, 20% PEG400, 70% (10% TPGS) and 5% (1% HPMCK100LV) were added to prepare a white uniform suspension.

2.4 Administration

After an overnight fast, the mice were administered by gavage at a dose of 100 mg/kg and a dose of 10 mL/kg.

3. Operation

Before administration and 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, 11.0h, and 24.0h after administration, 0.2 mL of blood was collected from the orbit of the gavage group, and EDTA-K2 anticoagulation test tubes were placed. , centrifuge at 11,000 rpm for 1 min (4°C), separate plasma within 1 h, and store at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions. Food was taken 2 hours after administration.

Determination of the content of the test compound in the plasma of SD rats after oral administration of different concentrations of drugs: take 20 μL of SD rat plasma at each time after administration, add 50 μL of internal standard solution (camptothecin 100 ng/mL), 200 μL of acetonitrile , vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 0.5 μL of the supernatant was taken from the plasma sample for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 5 Pharmacokinetic parameters of the disclosed compounds in SD rats

Conclusion: The disclosed compound 3-P1 has good drug metabolism and absorption in SD rats, and has the advantages of pharmacokinetics.

Test Example 6: Pharmacokinetic Evaluation of the Compounds of the Disclosure in Beagle Dogs

1. Abstract

Using beagle dogs as the test animals, the LC/MS/MS method was used to determine the drug concentrations in the plasma of the beagle dogs at different times after intragastric administration and intravenous injection of the test compounds. To study the pharmacokinetic behavior of the disclosed compounds in beagle dogs, and to evaluate their pharmacokinetic characteristics.

2. Test plan

2.1 Test Drugs

Compound 3-P1 .

2.2 Experimental animals

Eight beagle dogs, half male and half female, were divided into 2 groups of 4 dogs, provided by Shanghai Medicilon Bio-Pharmaceutical Co., Ltd.

2.3 Drug preparation

Weigh a certain amount of medicine, add 5% DMSO, 20% PG, 20% PEG400 and 55% normal saline to prepare a clear solution.

2.4 Administration

After an overnight fast, they were administered by intravenous injection and intragastric administration, respectively, at a dose of 0.5 mg/kg and 2 mg/kg, and the administration volume was 2 mL/kg and 5 mL/kg, respectively.

3. Operation

Before administration and 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, 12.0h, 24.0h after administration, 1.0 mL of blood was collected from the jugular vein or forelimb vein in the intragastric administration group. Put it in an EDTA-K2 anticoagulation test tube, centrifuge at 10,000 rpm for 5 min (4 °C), separate the plasma within 1 h, and store it at -80 °C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions. Food was taken 3 hours after administration.

Blood was collected in the intravenous administration group before administration and at 5min, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 12.0h, and 24.0h after administration, and the treatment was the same as the intragastric administration group.

Determination of the content of the test compound in the plasma of beagle dogs after oral administration and intravenous injection of drugs with different concentrations: take 30 μL of beagle dog plasma at each time after administration, add internal standard solution (warfarin 100ng/mL), 300 μL of methanol, vortexed for 1 minute, and centrifuged for 10 minutes (18000 g centrifugal force). Transfer 200 μL to a 96-well plate, and take 5 μL of the supernatant from the plasma sample for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 6 Pharmacokinetic parameters of the disclosed compounds in beagle dogs

Conclusion: The disclosed compound 3-P1 has good drug metabolism and absorption in beagle dogs, and has the advantages of pharmacokinetics.

Claims (23)

A compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

in, R ¹ is selected from

,

,

,

and

wherein L is the same or different at each occurrence, and each is independently selected from a bond, ( _CH2 ) _q , C(O), NH, and an oxygen atom; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁸ is the same or different at each occurrence and is each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, haloalkyl, pendant oxy, halogen, cyano, -NR ^dd R substituted with one or more substituents in ^ee , nitro, ^-ORcc , cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring C is containing at least one

The heterocyclyl group, wherein the S atom is used as the ring atom in the heterocyclyl group; R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom, a pendant oxy group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, -OR ^c , a hydroxyalkyl group, a cyano group, -NR ^d R ^c and nitro; Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R ² is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, nitro, -OR ^c , -S(O) _r R ^c , -NR ^{d Re} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C (O)OR ^c , -OC(O)OR ^c , -OC(O)NR ^{d Re} , -C(O)NR ^{d Re} , -NR ^f C(O)NR ^{d Re} , -NR ^f C (O) ^Rc , ^-NRfC (O) ^ORc , -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -(CH ₂ ) _p -heteroaryl groups are each independently optionally selected from a hydrogen atom, a pendant oxy group, a halogen, an alkyl group, a haloalkyl group, -OR ^cc , -NR ^dd R ^ee , -C(O)R ^cc , - ^substituted with one or more substituents of OC(O) ^Rcc , -C(O) ^ORcc , -C(O) ^NRddRee , cyano and nitro; R ³ is selected from alkyl, haloalkyl, -OR ^c , -S(O) _r R ^c , -NR ^f S(O) _r R ^c , -(CH ₂ ) _p -cycloalkyl, -(CH ₂ ) _p -heterocyclyl, -( _CH2 ) _p -aryl and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl are each independently optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, ^-ORcc , Substituted with one or more substituents of cyano, -NR ^dd R ^ee , nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R ⁴ is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, nitro, -OR ^c , -S(O) _r R ^c , -NR ^{d Re} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C (O)OR ^c , -OC(O)OR ^c , -OC(O)NR ^{d Re} , -C(O)NR ^{d Re} , -NR ^f C(O)NR ^{d Re} , -NR ^f C (O)R ^c and -NR ^f C(O)OR ^c ; X and Y are the same or different, and are each independently an N atom or CR ^x ; Rx ^is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, ^-ORc , cyano, nitro, -S(O ⁾ _rRc ^{, -NRdRe} , -NR ^f S(O) _r R ^c , -S(O) _r NR ^{d Re} , -C(O)R ^c , -OC(O)R ^c , -C(O)OR ^c , -OC( O) ^ORc , -OC(O) ^NRdRe , -C(O) ^NRdRe , ^-NRfC (O) ^NRdRe , ^{-NRfC ( O )Rc and -NRf} C(O)OR ^c ; wherein the alkyl group is optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, -OR ^cc , cyano, -NR ^dd R ^ee , nitro, cycloalkyl, hetero substituted with one or more substituents in cyclic, aryl and heteroaryl; R ^6a and R ^6b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -C(O)R ^c , -(CH ₂ ) _p - Cycloalkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl; wherein the alkyl, -( _CH2 ) _p -ring Alkyl, -( _CH2 ) _p -heterocyclyl, -( _CH2 ) _p -aryl, and -( _CH2 ) _p -heteroaryl are each independently optionally selected from hydrogen atoms, pendant oxy groups, halogens , alkyl, haloalkyl, hydroxyalkyl, -OR ^cc , cyano, -NR ^dd R ^ee , nitro, cycloalkyl, heterocyclyl, aryl, and one or more substituents in heteroaryl replaced; R ^7a and R ^7b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group , aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group , cyano, -NR ^dd R ^ee , nitro, -OR ^cc , cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents; ^R5 , ^R9 , and ^Rf are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally selected from a hydrogen atom, halogen, alkyl, haloalkyl, -OR ^cc , cyano, - Substituted with one or more substituents in NR ^{dd Ree} , nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ^c and R ^cc are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; wherein , the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, -NR ^dd R ^ee , nitro groups , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl; R ^d , R ^e , R ^dd and R ^ee are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, cyano, nitro , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2 or 3; p is 0, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5 or 6: r is 0, 1 or 2; s is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4 or 5. The compound represented by the general formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof The salt used is the compound represented by the general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its Medicinal salt:

in, X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in claim 1 . The compound represented by the general formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof The salt used, which is the compound represented by the general formula (II-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its Medicinal salt:

in, X, Ring A, Ring B, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , L, R ^a , R ⁸ , t, m and n are as defined in claim 1 . The compound represented by the general formula (I) according to any one of claims 1 to 3 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; preferably, Ring A is selected from thiazolyl, dihydropyrrolopyrazolyl, 1,2,4-oxadiazolyl, dihydropyrrolothiazolyl and dihydropyrrolooxazolyl; more preferably, ring A is selected from

,

,

,

,

and

; Optimally, ring A is selected from

,

and

. The compound represented by the general formula (I) according to any one of claims 1 to 4 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein each R ² is the same or different, and each is independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkane group; preferably, R ² is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 5 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from C _1-6 alkyl, C _1-6 haloalkyl and -OR ^c , and R ^c is C _1-6 alkyl; preferably, R ³ is -OR ^c , and R ^c is C _1-6 alkyl; more preferably, R ³ is -OR ^c , and R ^c is methyl. The compound represented by the general formula (I) according to any one of claims 1 to 6 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein each R ⁴ is the same or different, and each is independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkane group; preferably, R ⁴ is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 7 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein ^R5 is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 8 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein ^X is an N atom or CRx, and Rx ^is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 9 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein R ^6a and R ^6b are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 hydroxyalkane and -C(O)R ^c , and R ^c is a 3- to 8-membered cycloalkyl; preferably, R ^6a and R ^6b are different, and are each independently a hydrogen atom or -C(O)R ^c , and R ^c is a 3- to 6-membered cycloalkyl; more preferably, R ^6a and R ^6b are different and are each independently a hydrogen atom or -C(O)R ^c , and R ^c is selected from cyclopropyl. The compound represented by the general formula (I) according to any one of claims 1 to 10 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein R ^7a and R ^7b are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms, C _1-6 alkyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl and C _1-6 hydroxyalkyl; preferably, R ^7a and R ^7b are different, and are each independently a hydrogen atom or CD ₃ . The compound represented by the general formula (I) according to any one of claims 1 to 11 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein ^R8 is the same or different at each occurrence, and each independently is _C1-6 alkyl; preferably, ^R8 is methyl. The compound represented by the general formula (I) according to any one of claims 1, 3 to 11 or a tautomer, racemate, enantiomer, diastereomer, or tautomer, racemate, enantiomer, or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is the same or different at each occurrence, and each independently is ( _CH2 ) _q or C(O), and q is 1. The compound represented by the general formula (I) according to any one of claims 1 to 13 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

A compound represented by the general formula (IIa-1) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

in, R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS); X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in claim 2. A compound or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

A compound or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

A compound represented by the general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof method, which includes:

The compound of general formula (IIa-1) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt is deprotected R ^w , to obtain the compound of general formula (II-1) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof , in, R ^W is a protecting group; preferably, R ^W is tert-butyldimethylsilyl (TBS); X, Ring A, R ² to R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , m and n are as defined in claim 2. A pharmaceutical composition containing a compound represented by the general formula (I) as described in any one of claims 1 to 14 or a tautomer, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. A compound represented by general formula (I) as described in any one of claims 1 to 14 or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or mixture Use of the form, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as claimed in claim 19 in the manufacture of a medicament for inhibiting TYK2. A compound represented by general formula (I) as described in any one of claims 1 to 14 or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or Use of a mixture form, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 19, in the manufacture of a medicament for the treatment and/or prevention of a disease, disorder or condition mediated by TYK2. A compound represented by general formula (I) as described in any one of claims 1 to 14 or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 19, for the treatment and/or prevention of proliferative diseases, metabolic diseases, allergic diseases, inflammatory diseases or autoimmune diseases Use in medicine for disease. The use as claimed in claim 22, wherein the inflammatory disease or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory Enteropathy, Psoriasis/Psoriasis, Psoriatic Arthritis, Crohn's Disease, Sjögren's Syndrome, Systemic Disease Scleroderma, Ulcerative Colitis, Graves' Disease, Discoid Lupus Erythematosus, Adult Still disease, juvenile idiopathic arthritis, gout, gouty arthritis, sepsis, septic shock, shigellosis, pancreatitis, glomerulonephritis, idiopathic nephritis, autoimmune hemolytic anemia, autoimmune Neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, pulmonary hemorrhagic nephritis syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA Associated small vessel vasculitis, pemphigus, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pneumonia, autoimmune immune thyroiditis, autoimmune Autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy, preferably, the inflammatory disease or autoimmune disease is selected from rheumatoid arthritis, atopic dermatitis, psoriasis or inflammatory bowel disease The metabolic disease is diabetes; The proliferative disease is cancer, preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer, lung cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.