WO2021202652A1 - Tyrosine kinase 2 inhibitors, preparation methods and medicinal uses thereof - Google Patents

Abstract

This application discloses Tyk-2 inhibitors represented by the general formula (I) and analogs thereof, pharmaceutical compositions containing these compounds, method of preparing them, and use of these compounds as therapeutic agents for the treatment of diseases or conditions associated with Tyk-2 activity, such as autoimmune diseases and cancers.

Description

TYROSINE KINASE 2 INHIBITORS, PREPARATION METHODS AND MEDICINAL USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application No. 63/003,658, filed on April 1, 2020, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to compounds useful in the suppression of non-receptor tyrosine-protein kinase 2, also known as Tyrosine kinase 2 (Tyk2). The disclosure further provides pharmaceutical compositions containing these compounds and methods of using the pharmaceutical compositions in the treatment of various disorders related to the regulation of Tyk2 activity.

BACKGROUND OF THE DISCLOSURE

Cytokine signaling plays a pivotal role in controlling the growth, differentiation, function, and communication of immune cells. Multiple cytokine signaling transduction pathways are mediated by the actions of receptor-bound Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs) (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 ak, “JAK inhibition as a therapeutic strategy for immune and inflammatory diseases” Nat Rev Drug Discov. 2017, 17:78; Schwartz DM et ak, “Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases ” Nat Rev Rheumatol. 2016, 12: 25-36).

The JAKs are a family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that associate with the intracellular domains of cell surface cytokine receptors. Upon stimulation and oligomerization of these receptors, the JAK molecules are activated and serve as docking sites for subsequent recruitment and phosphorylation of STAT proteins. In turn, the phosphorylated STAT proteins then dimerize, translocate to the nucleus, and activate transcription of genes mediating cytokine-induced responses. These cytokine-mediated- JAK/STAT pathways are tightly regulated, and dysfunctional JAK/STAT activities have been demonstrated as hallmarks of numerous immunological and autoimmune disorders, inflammatory diseases, as well as cell transformation (Schwartz DM et ak, “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 major component in various cytokine pathways, resulting in the STAT-dependent gene transcription and specific functional responses of the cytokines, which include the Interleukin-12/-23 family (IL-12/IL-23, which share a common p40 subunit), the Type I interferon (IFN) family, as well as 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). The Tyk2-mediated signaling of cytokines play critical roles in autoimmune disorders and inflammatory disease pathogenesis. Specifically, IL-23 (a heterodimer that contains p40 and p19 subunits) is crucial for the differentiation and proliferation of T helper cells 17 (Th17), which are a key participant 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, which is composed of p40 and a unique p35 subunit, is important in regulating Th1 development and the IFN-γ secretion of 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). Through the mediation of Th1/Th17 responses, IL-12 and IL-23 play essential roles in a variety of inflammatory diseases, such as Psoriasis (Ps), Lupus, Inflammatory Bowel Disease (IBD), Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), etc (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 L. C et al., “IL-23: One cytokine in control of autoimmunity” Eur. J. Immunol.2012, 42: 2263–2273; Craig A. M 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, deficiency of either the common subunit P40, or shared receptor IL23R, of IL12 and IL23, were found to protect mice from various autoimmune diseases (Ps, Lupus, IBD, MS, RA, etc) (Kyttaris VC et al., “Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice” J Immunol. 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, independently 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 were observed in the lesional skin of psoriatic patients, which was then lowered after various therapeutic 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). Moreover, blocking monoclonal antibodies directed against the IL-12/IL-23 common subunit p40 (Ustekinumab, Briakinumab, etc), or IL-23 specific subunit p19 (Tildrakizumab, Risankizumab, etc), were proven to be clinically efficacious in treating psoriasis, Crohn’s disease, etc (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). Meanwhile, the Type I IFN family members (IFN-α, -β, -ε, -κ, and -ω), acting through a heterodimer IFN receptor (IFNAR), are not only important mediators for both innate and adaptive immunities by activating numerous factors in immune responses, but also effective enhancers of autoantigen expression and release, thus becoming crucial participants in autoimmune disease amplification (Lionel B.I. et al., “Regulation of type I interferon responses” Nat Rev Immunol. 2014, 14: 36–49; John C. H. et al., “Type I interferons: crucial 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 IFNs in pathogenesis of Systemic Lupus Erythematosus (SLE) is evidenced by the observation that deletion of the IFNAR in lupu-prone NZB mice provides a high degree of protection from lupus severity and mortality (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 increased type-I IFN regulated gene expression in peripheral blood mononuclear cells (PBMCs) and affected organs were reported in majority of patients. Furthermore, several studies reported the activation of the Type I IFN genes are well-correlated with activity and the 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). Emerging research evidence demonstrated the importance of Tyk2 in the pathogenesis of afore-mentioned autoimmune diseases. For example, Tyk2-deficient or -chemically inhibited rodents were revealed to be resistant to experimental autoimmune disease models of psoriasis, MS, and IBD (Michael P. S. et 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; Miao W et al., “Potent and Selective Tyk2 Inhibitor Highly Efficacious in Rodent Models of Inflammatory Bowel Disease and Psoriasis” Arthritis Rheumatol. 2016, 68, suppl 10). In human studies, catalytically impaired Tyk2 variants (rs12720356, and rs34536443) are found to be protective against childhood-, as well as adult- onset of SLE in the Mexican Mestizo population (Cecilia C.C. 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 were also shown to be associated with SLE in patients of Nordic ancestry, UK, and Han Chinese populations. More broadly, Genome-wide association studies (GWAS) have identified several inactive variants of Tyk2 to be significantly associated with inflammatory diseases, including multiple sclerosis, psoriasis, Crohn’s disease, lupus, and rheumatoid arthritis, further indicating the impact of Tyk2 in a broad scope of autoimmune disorders (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 signals required to generate specialized T cell subsets” Front Immunol. 2019, 25;10:44). Therefore, it is rationalized that agents that suppress the action of Tyk2-mediated cytokine signaling pathways may have potential therapeutical benefit in human autoimmune diseases. Indeed, a highly selective allosteric Tyk2 inhibitor, BMS986165, was shown to effectively block IL-12/IL-23 and Type I IFN pathways and thus demonstrate substantial in vivo efficacy in numerous experimental autoimmune disease models (psoriasis, SLE, and IBD) (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). Moreover, the Phase 2 trial results of this agent was announced to achieve ≥75% and 90% reduction in the Psoriasis Area and Severity Index (PASI 75, PASI 90) in patients with moderate to severe plaque psoriasis with a favorable risk-benefit profile (Kim P. et al., “Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis” N Engl J Med. 2018, 379:1313-1321), further supporting the notion of Tyk2 as a promising therapeutic target in the area of autoimmune- disorders. SUMMARY OF THE DISCLOSURE The present disclosure, in one aspect, provides a compound of formula (I):

or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: G¹ is N or CH; G² and G³ are identical or different, and each is independently selected from the group consisting of NR⁶, CR⁷R⁸, O, S and S(=O)2; provided that at least one of G¹, G² and G³ is heteroatom; L is a bond or alkylene, wherein the alkylene is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R¹ is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R² and R³ are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; R⁴ at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁵ at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to three, groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, hydroxyalkyl, -C(O)R⁹, -C(O)OR⁹, -C(O)NR¹⁰R¹¹,cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to three, groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁷ and R⁸ are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to three, groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁹ is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is each optionally independently substituted with one or more, sometimes preferably one to three, groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R¹⁰ and R¹¹ are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; n is 0 or 1; r is 0, 1, 2, 3, 4 or 5; and t is 0, 1, 2, 3 or 4. In another aspect, the present disclosure also provides a pharmaceutical composition, comprising a compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a method of treating a Tyk2- mediated disorder, disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing the same. In another aspect, the present disclosure relates to a method of treating proliferative diseases, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or pharmaceutical composition containing the same. In another aspect, the present disclosure relates to a method of treating autoimmune and inflammatory diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or pharmaceutical composition containing the same. Wherein the autoimmune and inflammatory diseases is selected from arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren’s syndrome, systemic scleroderma, ulcerative colitis, Graves’ disease, discoid lupus erythematosus, adult onset stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type I diabetes, insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis, glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyneuropathy(CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy. In another aspect, the present disclosure relates to a method of treating proliferative diseases, which include cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or pharmaceutical composition containing the same. wherein the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, tubal tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, hepatocellular carcinoma, papillomatosis, head and neck tumor, leukemia, lymphoma, myeloma and non- small cell lung cancer. DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present disclosure provides a compound of formula (I):

( I ) , or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: G¹ is N or CH; G² and G³ are identical or different, and each is independently selected from the group consisting of NR⁶, CR⁷R⁸, O, S and S(=O)₂; provided that at least one of G¹, G² and G³ is heteroatom; L is a bond or alkylene, wherein the alkylene is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R¹ is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R² and R³ are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; R⁴ at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁵ at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, hydroxyalkyl, -C(O)R⁹, -C(O)OR⁹, -C(O)NR¹⁰R¹¹,cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁷ and R⁸ are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁹ is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R¹⁰ and R¹¹ are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; n is 0 or 1; r is 0, 1, 2, 3, 4 or 5; and t is 0, 1, 2, 3 or 4. In some embodiments, in the compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, ring A is 5 or 6-member heteroaryl; and preferably triazolyl. In some embodiments, in the compound of formula ( I ), or a tautomer, cis- or trans- isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, L is bond or CH₂. In some embodiments, the compound of formula ( I ) is a compound of formula (II):

, or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: q is 0 or 1; and G¹, G², G³, R¹ to R⁵, n and t are each as defined in formula ( I ) above. In some embodiments, in the compound of formula ( I ) or formula ( II ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof,

is selected from the group consisting of and G², G³, R^{7 8}

and R are as defined in formula ( I ). In some embodiments, in the compound of formula ( I ) or formula ( II ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable saltor solvate thereof,

is selected from the group consisting of

and R⁶, R⁷ and R⁸ are as defined in formula ( I ). In some embodiments, the compound of formula ( I ) or formula ( II ) is a compound of formula ( III ):

or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ to R⁵, R⁷ and R⁸ are each as defined in formula ( I ). In some embodiments, the compound of formula ( I ) or formula ( II ) is a compound of formula ( IV ):

or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: q is 0 or 1; and R¹ to R⁶ are each as defined in formula ( I ). In some embodiments, in the compound of formula ( I ), formula ( II ), formula ( III ) or formula ( IV ) or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, R¹ is selected from the group consisting of alkyl, deuterated alkyl and haloalkyl; in some embodiments preferably C_1-6alkyl, deuterated C_1-6alkyl or halo C_1-6alkyl. In some embodiments, in the compound of formula ( I ), formula ( II ), formula ( III ) or formula ( IV ) or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, R² and R³ are hydrogen. In some embodiments, in the compound of formula ( I ), formula ( II ), formula ( III ) or formula ( IV )or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, R⁴ at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl and hydroxyalkyl; in some embodiments preferably hydrogen or C_1-6alkoxy; in some embodiments preferably C_1-6alkoxy. In some embodiments, in the compound of formula ( I ), formula ( II ), formula ( III ) or formula ( IV )or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, R⁵ at each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl and hydroxyalkyl; in some embodiments preferably hydrogen or C_1-6alkyl; in some embodiments preferably C_1-6alkyl. In some embodiments, in the compound of formula ( I ), formula ( II ), or formula ( IV ) or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, R⁶ is selected from the group consisting of hydrogen, alkyl, haloalkyl, -C(O)R⁹ and -C(O)OR⁹; preferably, R⁶ is -C(O)R⁹ or -C(O)OR⁹; and R⁹ is as defined above. In some embodiments, in the compound of formula ( I ), formula ( II ), or formula ( III ) or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, R⁷ and R⁸ are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen and hydroxyl. In some embodiments, in the compound of formula ( I ) or formula ( II ) or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, G¹ is CH. In some embodiments, in the compound of formula ( I ) or formula ( II ) or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, n is 1. In some embodiments, in the compound of formula ( II ) or a tautomer, cis- or trans- isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein G¹ is CH; G² and G³ are identical or different, and each is independently selected from the group consisting of NR⁶, CR⁷R⁸, O, S and S(=O)2; provided that at least one of G² and G³ is heteroatom; R¹ is selected from the group consisting of C_1-6alkyl, deuterated C_1-6alkyl and halo C_1-6alkyl; R² and R³ are hydrogen; R⁴ is independently hydrogen or C_1-6alkoxy; R⁵ is independently hydrogen or C_1-6alkyl; t is 0 or 1; q is 0 or 1; and n is 1. With regards to any of the groups defined herein, the present disclosure encompasses any plausible combinations to the extent that such combinations do not violate basic chemical bonding principles and provide stable compounds. Table A. Exemplified compounds of the disclosure include, but are not limited to:

In another aspect, this disclosure provides a compound of formula (IA):

, or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: R^w is alkoxy or hydroxyl; and ring A, G¹, G², G³, L, R² to R⁵, n, r and t are each as defined in formula ( I ) above. In another aspect, this disclosure provides a compound of formula (IIA):

, or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: R^w is alkoxy or hydroxyl; and G¹, G², G³, R² to R⁵, q, n and t are each as defined in formula ( II ) above. In another aspect, this disclosure provides a compound of formula (IIIA): R

, or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: R^w is alkoxy or hydroxyl; and R² to R⁵, R⁷ and R⁸ are each as defined in formula ( III ) above. In another aspect, this disclosure provides a compound of formula (IVA):

, or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: R^w is alkoxy or hydroxyl; and R² to R⁶ and q are each as defined in formula ( IV ) above. In another aspect, this disclosure provides a compound of formula (IVB):

, or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ to R⁵ and q are each as defined in formula ( IV ) above. Exemplified intermediate compounds of the disclosure according to formula (IA) include, but are not limited to:

; or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, this disclosure provides a process of preparing the compound of formula (I), or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IA) with a compound of R¹-NH₂ to obtain the compound of formula ( I ); wherein: R^w is alkoxy or hydroxyl; and ring A, G¹, G², G³, L, R¹ to R⁵, n, r and t are each as defined in formula (I) above. In another aspect, this disclosure provides a process of preparing a compound of formula (II), or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IIA) with a compound of R¹-NH₂ to obtain the compound of formula ( II ); wherein: R^w is alkoxy or hydroxyl; and G¹, G², G³, R¹ to R⁵, q, n and t are each as defined in formula (II) above. In another aspect, this disclosure provides a process of preparing a compound of formula (III), or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IIIA) with a compound of R¹-NH₂ to obtain the compound of formula ( III ); wherein: R^w is alkoxy or hydroxyl; and R¹ to R⁵, R⁷ and R⁸ are each as defined in formula (III) above. In another aspect, this disclosure provides a process of preparing a compound of formula (IV), or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of: R

( IVA ) ( IV ) reacting a compound of formula (IVA) with a compound of R¹-NH₂ to obtain the compound of formula ( IV ); wherein: R^w is alkoxy or hydroxyl; and R¹ to R⁶ and q are each as defined in formula (IV) above. In another aspect, this disclosure provides a process of preparing a compound of formula (IV), or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IVB) with a compound of R⁶-X to obtain the compound of formula ( IV ); wherein: X is halogen; preferably Cl; and R¹ to R⁶ and q are each as defined in formula (IV) above. In another aspect, the present disclosure provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I), formula ( II ), formula ( III ), formula ( IV ) or Table A, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a method of treating a Tyk2- mediated disorder, disease, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula ( I ), formula ( II ), formula ( III ), formula ( IV ) or Table A, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof , solvate or prodrug thereof. In another aspect, the present disclosure provides a method of treating a Tyk2- mediated disorder, disease, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition containing a compound of formula ( I ), formula ( II ), formula ( III ), formula ( IV ) or Table A,or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof , solvate or prodrug thereof. In another aspect, the present disclosure discloses use of a compound of formula ( I ), formula ( II ), formula ( III ), formula ( IV ) or Table A, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for the treatment of an Tyk2-mediated disorder, disease, or condition. The Tyk2-mediated disorder, disease, or condition that may be treated according to the present invention includes, but is not limited to, proliferative diseases, metabolic, allergic, autoimmune and inflammatory diseases. The autoimmune and inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren’s syndrome, systemic scleroderma, ulcerative colitis, Graves’ disease, discoid lupus erythematosus, adult onset stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type I diabetes, insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis, glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyneuropathy(CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy. The proliferative diseases include cancer, which can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, tubal tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, hepatocellular carcinoma, papillomatosis, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer. In another aspect, the present disclosure provides a method of treating any of aforementioned Tyk2-mediated disorder, disease, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula ( I ), formula ( II ), formula ( III ), formula ( IV ) or Table A, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with a second therapeutic agent or a different treatment method. The active compounds can be formulated in a form suitable for administration by any suitable route using conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (for example, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation. The compounds of the disclosure may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches, or syrups. The dosage of the compound or composition used in the method of treatment of the disclosure will generally vary with the severity of the disease, the weight of the patient and the relative efficacy of the compound. However, as a general guide, the active compound is preferably in the form of a unit dose or in such a way that the patient can self-administer in a single dose. The unit dose of the compound or composition of the present disclosure can be expressed in the form of tablets, capsules, cachets, bottled potions, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. A suitable unit dose may be from 0.1 to 1000 mg. In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrating agents, or excipients. Depending on the method of administration, the composition may contain from 0.1 to 99%, sometimes preferably 1 to 70%, by weight of active compound. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period. Oral formulations may also be provided 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 carrier or an oil vehicle. Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweetening agents. Oil suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of antioxidants. The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant. The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection solution or microemulsion may be injected into the bloodstream of the patient by local large-scale 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, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS. TM.5400 intravenous pump. The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable water or oily suspension 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 prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blending fixing oil can be used. In addition, fatty acids can also be prepared for injection. 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 dissolve in the rectum to release the drug. Compounds of the present disclosure can be administered by adding water to prepare water-suspendable dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent or one or more preservatives. As is well known to those skilled in the art, the dosage of a drug depends on a number of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, and the patient's behavior , The patient's diet, the time of administration, the manner of administration, the rate of excretion, the combination of drugs, etc .; in addition, the best treatment such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan. Definitions Unless otherwise stated, the terms used in the specification and claims have the meanings described below. “Alkyl” refers to a saturated aliphatic hydrocarbon group including C₁-C₂₀ straight chain and branched chain groups. Preferably an alkyl group is an alkyl having 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms. In some embodiments, sometimes preferably, an alkyl group is an alkyl having 1 to 8 carbon atoms. Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2- trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 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, 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 the isomers of branched chain thereof. In some embodiments, sometimes more preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, sec-butyl, 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-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3- dimethylbutyl,etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point, preferably the substituent group(s) is one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group. “Alkenyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3- butenyl, etc., preferably C_2-20 alkenyl, more preferably C_2-12 (for example, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) alkenyl, and sometimes more preferably C2-6 alkenyl, and sometimes even more preferably C_2-4 alkenyl. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of halogen, alkoxy, alkynyl, alkylsulfo, alkylamino, thiol, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group. “Alkynyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl etc., preferably C_2-20 alkynyl, more preferably C_2-12 (for example, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) alkynyl, and sometimes preferably C_2-6 alkynyl, and sometimes even more preferably C_2-4 alkynyl. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of alkenyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxy, cycloalkylthio and heterocylic alkylthio. “Alkylene” refers to a saturated linear or branched divalent aliphatic hydrocarbon group, derived by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms of the parent alkane. The straight or branched chain group contains 1 to 20 carbon atoms, preferably 1 to 12 (for example, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) carbon atoms, sometimes more preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH₂-), 1,1-ethylene (-CH(CH₃)-), 1,2-ethylene (- CH₂CH₂)-, 1,1-propylene (-CH(CH₂CH₃)-), 1,2-propylene (-CH₂CH(CH₃)-), 1,3-propylene (- CH₂CH₂CH₂-), and 1,4-butylidene (-CH₂CH₂CH₂CH₂-), etc. The alkylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is (are) preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of selected from alkenyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxy, cycloalkylthio and heterocylic alkylthio. “Alkenylene” refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C_2-20 alkenylene, more preferably C_{2- 12} (for example, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) alkenylene, sometimes more preferably C_2-6 alkenylene, and sometimes even more preferably C_2-4 alkenylene. Non- limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, - CH=CHCH₂-, -CH=CHCH₂CH₂-, and -CH₂CH=CHCH₂-, etc. The alkenylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxy, cycloalkylthio and heterocylic alkylthio. “Cycloalkyl” refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 (for example, including 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) carbon atoms, more preferably 3 to 10 carbon atoms, sometimes more preferably 3 to 8 (for example, 3, 4, 5, 6, 7 or 8) carbon atoms, and sometimes even more preferably 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring. “Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom), wherein one or more rings can contain one or more double bonds. Preferably a spiro cycloalkyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbon), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of common spiro atoms, a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4- membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl. Representative examples of spiro cycloalkyl include, but are not limited to, the following groups:

_. “Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds. Preferably, a fused cycloalkyl group is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbon), more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of membered rings, fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following groups:

“Bridged Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds. Preferably, a bridged cycloalkyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12,13 and 14 carbon), and more preferably 7 to 10 (for example, 7, 8, 9 and 10) membered. According to the number of membered rings, bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following groups:

The cycloalkyl may also include the cycloalkyl said above which fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl. Representative examples include, but are not limited to indanyl, tetrahydronaphthalene, benzocycloheptyl and so on. The cycloalkyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group. “Heterocyclyl” refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N, O, S, S(=O) and S(=O)2 as ring atoms, but excluding -O-O-, -O-S- or -S-S- in the ring, the remaining ring atoms being C. Preferably, heterocyclyl is a 3 to 12 membered having 1 to 4 (example 1, 2, 3 or 4) heteroatoms; more preferably a 3 to 10 (example 3, 4, 5, 6, 7, 8, 9 and 10) membered having 1 to 3 heteroatoms; more preferably a 6 to 10 membered having 1 to 3 heteroatoms; most preferably a 5 to 6 membered having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on. Polycyclic heterocyclyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring. “Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of N, O, S, S(=O) and S(=O)2 as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds. Preferably a spiro heterocyclyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of common spiro atoms, spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 3- membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4- membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5- membered/6-membered mono-spiro heterocyclyl. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:

. “Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, and wherein said rings have one or more heteroatoms selected from the group consisting of N, O, S, S(=O) and S(=O)2 as ring atoms, the remaining ring atoms being C. Preferably a fused heterocyclyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of membered rings, fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to, the following groups:

“Bridged Heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, and the rings have one or more heteroatoms selected from the group consisting of N, O, S, S(=O) and S(=O)₂ as ring atoms, the remaining ring atoms being C. Preferably a bridged heterocyclyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of membered rings, bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following groups:

. The ring of said heterocyclyl include the heterocyclyl said above which fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Representative examples include, but are not limited to the following groups:

substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxy, cycloalkylthio and heterocylic alkylthio. “Aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi- electron system. Preferably aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl include the aryl said above which fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Representative examples include, but are not limited to, the following groups:

The aryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxy, cycloalkylthio and heterocylic alkylthio. “Heteroaryl” refers to an aryl system having 1 to 4 (example 1, 2, 3 and 4)heteroatoms selected from the group consisting of O, S and N as ring atoms and having 5 to 14 (for example, including 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms) annular atoms. Preferably a heteroaryl is 5- to 10- membered (example 5, 6, 7, 8, 9 and 10), more preferably 5- or 6- membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl include the heteroaryl said above which fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples include, but are not limited to, the following groups:

The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxy, cycloalkylthio and heterocylic alkylthio.“Alkoxy” refers to both an -O-(alkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy and butoxy, and the like. The alkoxy can be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, independently selected from the group consisting of alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxy, cycloalkylthio and heterocylic alkylthio. “Bond” refers to a covalent bond using a sign of “—”. “Haloalkyl” refers to an alkyl group substituted by one or more halogen(s), wherein alkyl is as defined above. “Deuterated alkyl” refers to an alkyl group substituted by one or more deuterium atom, wherein alkyl is as defined above. “Hydroxyalkyl” refers to an alkyl group substituted by one or more hydroxyl group, wherein alkyl is as defined above. “Hydroxyl” refers to an -OH group. “Halogen” refers to fluoro, chloro, bromo or iodo atoms. “Amino” refers to a -NH₂ group. “Cyano” refers to a -CN group. “Nitro” refers to a -NO₂ group. “Oxo” refers to a =O group. “Carboxyl” refers to a -C(O)OH group. “Alkoxycarbonyl” refers to a -C(O)O(alkyl) or –C(O)O(cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above. “Optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. For example, “the heterocyclic group optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl. “Substituted” refers to one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable. A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present disclosure or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity. “Pharmaceutically acceptable salts” refer to salts of the compounds of the disclosure, such salts being safe and effective when used in a mammal and have corresponding biological activity. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable group with a suitable alkaline or acid. Alkalines commonly employed to form pharmaceutically acceptable salts include inorganic alkalines such as sodium, potassium, lithium, calcium, magnesium, or ammonium hydroxide; organic ammonium hydroxide such as tetramethylammonium or tetraethylammonium hydroxide, as well as organic alkalines such as various organic amines, including, but not limited to, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen bisulfide, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids. As a person skilled in the art would understand, the compounds of formula (I) or pharmaceutically acceptable salts thereof disclosed herein may exist in prodrug or solvate forms, which are all encompassed by the present disclosure. The term “solvate,” as used herein, means a physical association of a compound of this disclosure with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example, when one or more, preferably one to three, solvent molecules are incorporated in the crystal lattice of the crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art. “Prodrug” refers to compounds that can be transformed in vivo to yield the active parent compound under physiological conditions, such as through hydrolysis in blood. The term “pharmaceutically acceptable,” as used herein, refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term “therapeutically effective amount,” as used herein, refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a sustained reduction in viral load. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. The term “treat”, “treating”, “treatment”, or the like, refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition. In addition, the compounds of present disclosure may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it. As used herein, the singular forms “a”, “an”, and “the” include plural reference, and vice versa, unless the context clearly dictates otherwise. The term “subject” or “patient”, as used herein, refers to a human or a mammalian animal, including but not limited to dogs, cats, horses, cows, monkeys, or the like. When the term “about” is applied to a parameter, such as pH, concentration, temperature, or the like, it indicates that the parameter can vary by ±10%, and some times more preferably within ±5%. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting. SYNTHESIS METHODS For preparing compounds of the present invention, one aspect of the present invention includes, but is not limited to, the following synthetic methods: Scheme 1 A process of preparing a compound of formula (I), or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IA) with a compound of R¹-NH₂ to obtain the compound of formula ( I ), under acidic conditions; wherein: R^w is alkoxy or hydroxyl; and ring A, G¹, G², G³, L, R¹ to R⁵, n, r and t are each as defined in formula (I) above. Scheme 2 A process of preparing a compound of formula (II), or a tautomer, cis- or trans-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IIA) with a compound of R¹-NH₂ to obtain the compound of formula ( II ) , under acidic conditions; wherein: R^w is alkoxy or hydroxyl; and G¹, G², G³, R¹ to R⁵, q, n and t are each as defined in formula (II) above. Scheme 3 A process of preparing a compound of formula (III), or a tautomer, cis- or trans- isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IIIA) with a compound of R¹-NH₂ to obtain the compound of formula ( III ) , under acidic conditions; wherein: R^w is alkoxy or hydroxyl; and R¹ to R⁵, R⁷ and R⁸ are each as defined in formula (III) above. Scheme 4 A process of preparing a compound of formula (IV), or a tautomer, cis- or trans- isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of: R

( IVA ) ( IV ) reacting a compound of formula (IVA) with a compound of R¹-NH₂ to obtain the compound of formula ( IV ) , under acidic conditions; wherein: R^w is alkoxy or hydroxyl; and R¹ to R⁶ and q are each as defined in formula (IV) above. Scheme 5 A process of preparing a compound of formula (IV), or a tautomer, cis- or trans- isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising a step of:

reacting a compound of formula (IVB) with a compound of R⁶-X to obtain the compound of formula ( IV ), under alkaline conditions or acidic conditions; wherein: X is halogen; preferably Cl; and R¹ to R⁶ and q are each as defined in formula (IV) above. The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to trimethylamine, triethylamine, pyridine, N, N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, sodium acetate, potassium acetate, sodium tert-butanol or potassium tert-butanol; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably, for scheme 5, the reagents is trimethylamine or N, N-diisopropylethylamine. The reagents providing acidic conditions in the above synthesis scheme include but are not limited to acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, magnesium chloride, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid and nitric acid; preferably, for Scheme 1 to 4, the reagents is magnesium chloride; for Scheme 5, the reagent is trifluoroacetic acid. The reactions above are preferably conducted in one or more solvents, which include but are not limited to acetic acid, trifluoroacetic acid, methanol, ethanol, butanol, dimethyl ether, acetonitrile, petroleum ether, ethyl acetate, n-hexane, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N,N-dimethylformamide N,N- dimethylacetamide, 1,2-dibromoethane and the mixture thereof. EXAMPLES The following examples serve to illustrate the invention, but the examples should not be considered as limiting. If specific conditions for the experimental method are not specified in the examples of the present disclosure, they are generally in accordance with conventional conditions or recommended conditions of the raw materials and the product manufacturer. The reagents without a specific source indicated are commercially available, conventional reagents. The structures of compounds were determined by mass spectrometry (MS) and or nuclear magnetic resonance (NMR). NMR shift (δ) is given in units of 10^-6 (ppm). The mass spectrum (MS) was determined using a Shimadzu LCMS-2020 liquid chromatography-mass spectrometer. The NMR measurement was performed on a Bruker AVANCE-400 and 500 Ultrashield nuclear magnetic resonance spectrometer. The solvents were deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl₃) and deuterated methanol (CD3OD) Silane (TMS). HPLC was performed using a Shimadzu OPTION BOX-L high pressure liquid phase Chromatograph (Gemini 5um NX-C18100x21.2mm column). Thin-layer chromatography (TLC) silica gel plates used were Agela Technologies T- CSF10050-M silica gel plate with size of 50 mm, Column chromatography was commonly done using CombiFlash Rf+ Automated Flash Chromatography System (TELEDYNE ISCO) with Agela Technologies Flash Column Silica – CS prepacked columns. Known starting materials of the present disclosure may be synthesized according to methods known in the art or may be purchased from Acros Organics, Sigma-Aldrich Chemical Company, AstaTech and other companies. Unless otherwise specified in the examples, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask connected to a volume of about 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction bottle connected to a volume of about 1 L hydrogen balloon. Hydrogenation reaction was usually evacuated, filled with hydrogen, repeated 3 times. The microwave reaction used a CEM Discover-S 908860 microwave reactor. Unless otherwise specified in the examples, the reaction temperature was room temperature and was 20 ° C to 30 ° C. The progress of the reaction in the examples was monitored using thin layer chromatography (TLC), developing solvent for the reaction, a column chromatography eluent for purifying compound, and developing system for thin-layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: dichloromethane / ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compound. A small amount of triethylamine and acetic acid and other alkaline or acidic reagents can be used for adjustment. CH₃NH₂ is methyl amine, CD₃NH₂ is methyl-d₃ amine, DCM is dichloromathene, DIPEA is diisopropylethylamine, DMSO is dimethyl sulfoxide, EtOAc is ethyl acetate, MgSO₄ is magnesium sulfate, Pd2(dba)₃ is tris(dibenzylideneacetone)dipalladium(0), TEA is triethylamine, TFA is trifluoroacetic acid, THF is tetrahydrofuran, Xantphos is 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, and MS is mass spectroscopy with (+) referring to the positive mode which generally gives a M+1 absorption where M = the molecular mass. Example 1 6-(azetidine-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 1

Step 1 Methyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine- 3-carboxylate 1b A mixture of methyl 4,6-dichloropyridazine-3-carboxylate 1a (2.05 g, 10 mmol), 2- methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (204 g, 10 mmol), DIPEA (4 g, 30 mmol) in acetonitrile (20 mL) was heated with stirring in a sealed pressure vessel at 130°C for 24 h. The reaction mixture was cooled to room temperature and the solvents were removed by rotavapor in vacuo. The residue was purified with flash chromatography (silica 20-45micron, hexanes/EtOAc) to give 1b as a pale yellow solid (820 mg, yield: 45%). MS (ESI): m/z=375 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ: 9.81 (s, 1H), 8.58 (s, 1H), 7.78 (d, 1H), 7.57 (d, 1H), 7.32 (t, 1H), 7.08 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.71 (s, 3H). Step 2 Methyl 6-(azetidine-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)pyridazine-3-carboxylate 1c Compound 1b (step 1, 350 g, 0.94 mmol) and azetidine-1-carboxamide (140 mg, 1.4 mmol) were dissolved in dioxane (6 mL) followed by addition of Pd₂(dba)₃ (50 mg, 0.055 mmol), Xantphos (50 mg, 0.086 mmol), and cesium carbonate (611 mg, 1.88 mmol). The mixture was degassed by bubbling nitrogen gas through the mixture for 5 min. The reaction vessel was sealed and heated to 100 °C for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, partitioned between EtOAc (15 mL) and water (10 mL). The organic phase was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 1c as a tan solid (100 mg, yield: 24%). MS (ESI): m/z=439 [M+1]. ¹H NMR (400 MHz, CDCl3) δ: 9.97 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.40 (br, 1H), 7.20 (t, 1H), 4.07 (t, 4H), 3.97 (s, 3H), 3.94 (s, 3H), 3.70 (s, 3H), 2.22-2.30 (m, 2H). Step 3 6-(azetidine-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 1 Compound 1c (8 mg, 0.018 mmol) was dissolved in methylamine in THF (2N solution, 2 mL). Magnesium chloride (3.45 mg, 0.036 mmol) was added and the mixture was stirred for 2h. After the removal of the volatile solvent in vacuo, the residue was purified by column chromatography (hexane/EtOAc) to afford 1 as a white solid (6 mg, yield: 75%). MS (ESI): m/z=438 [M+1]. ¹H NMR (400 MHz, CDCl3) δ: 10.87 (s, 1H), 8.02 (s, 3H), 7.69 (d, 1H), 7.46 (d, 1H), 7.17 (t, 1H), 7.06 (s, 1H), 4.04 (t, 4H), 3.92 (s, 3H), 3.74 (s, 3H), 2.22-2.29 (m, 2H). Example 2 6-(azetidine-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-(methyl-d₃)pyridazine-3-carboxamide 2

Example 2 was prepared based on the same procedure described in step 3 of example 1 by using CD₃NH₂ instead of CH₃NH₂ in THF (2N). MS (ESI): m/z=441 [M+1]. ¹H NMR (400 MHz, CDCl3) δ: 10.89 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.69 (d, 1H), 7.46 (d, 1H), 7.32 (s, 1H), 7.17 (t, 1H), 4.06 (t, 4H), 3.92 (s, 3H), 3.74 (s, 3H), 2.21-2.29 (m, 2H). Examples 3 to 16 (Table 1) were prepared from 1b and corresponding amide based on the similar conditions described in steps 2 and 3 of example 1. Table 1. Compounds of formula:

Example 17 6-(2-(azetidin-3-yl)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 17

Compound 11 (5 mg, 0.009 mmol) was stirred in a mixture of TFA (0.2 mL) and DCM (0.2 mL) for 2 h. The mixture was concentrated in vacuo to afford 17 as a TFA salt (5 mg, yield: 98%). MS (ESI): m/z=452 [M+1]. ¹H NMR (400 MHz, CD₃OD) δ: 8.49 (s, 1H), 7.72 (d, 1H), 7.49 (d, 1H), 7.28 (s, 1H), 7.24(t, 1H), 4.09 (t, 2H), 3.88 (s, 3H), 3.84 (t, 2H), 3.64 (s, 3H), 3.23-3.28 (m, 1H), 2.89 (d, 3H), 2.82 (d, 2H). Example 18 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-(2-(1- (3,3,3-trifluoropropanoyl)azetidin-3-yl)acetamido)pyridazine-3-carboxamide 18

3,3,3-Trifluoropropanoyl chloride (1.75 mg, 0.012 mmol) in DCM (0.1 mL) was added a mixture of 17 (4.5 mg, 0.01 mmol) and trimethylamine (2 mg, 0.02 mmol) in DCM (2 mL) at room temperature. The mixture was stirred for 60 min at room temperature and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc) to afford 18 as a white solid (4 mg, yield: 71%). MS (ESI): m/z=562 [M+1]. ¹H NMR (400 MHz, CDCl3) δ: 10.99 (s, 1H), 9.07 (s, 1H), 8.05 (s, 1H), 7.99 (br, 1H), 7.97 (br, 1H), 7.78 (b, 1H), 7.39 (d, 1H), 7.21(t, 1H), 4.34 (t, 1H), 4.16 (t, 1H), 3.94 (s, 3H), 3.89 (t, 1H), 3.87 (s, 3H), 3.85 (t, 1H), 3.01-2.98 (m, 1H), 2.97 (d, 3H), 2.78-2.88 (m, 4H). Example 19 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-(2-(1- (2,2,2-trifluoroethyl)azetidin-3-yl)acetamido)pyridazine-3-carboxamide 19

2,2,2-Trifluoroethyl trifluoromethanesulfonate (4.6 mg, 0.02 mmol) was added into a solution of 17 (4.5 mg, 0.01 mmol) and DIPEA (2.6 mg, 0.02 mmol) in DCM (3 mL). The mixture was stirred at room temperature overnight, washed with water. The organic phase was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc) to afford 19 as a white solid (3 mg, yield: 56%). MS (ESI): m/z=534 [M+1].¹H NMR (400 MHz, CDCl₃) δ: 10.92 (s, 1H), 8.95 (s, 1H), 8.07 (s, 1H), 8.07 (br, 1H), 8.03 (s, 1H), 7.75 (d, 1H), 7.42 (d, 1H), 7.22(t, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 3.54 (t, 2H), 3.08 (t, 2H), 2.97 (d, 3H), 2.78-2.95 (m, 5H). Example 20 Ethyl 3-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6- (methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)azetidine-1-carboxylate 20

Ethyl carbonochloridate (1.2 mg, 0.012 mmol) in DCM (0.1 mL) was added to a mixture of 17 (4.5 mg, 0.01 mmol) and trimethylamine (2 mg, 0.02 mmol) in DCM (2 mL) at room temperature. The mixture was stirred for 60 min and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc) to afford 20 as a white solid (3.5 mg, yield: 67%). MS (ESI): m/z=524 [M+1]. Example 21 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-(2-(1- pivaloylazetidin-3-yl)acetamido)pyridazine-3-carboxamide 21

Pivaloyl chloride (1.4 mg, 0.012 mmol) in DCM (0.1 mL) was added to a mixture of 17 (4.5 mg, 0.01 mmol) and trimethylamine (2 mg, 0.02 mmol) in DCM (2 mL) at room temperature. The mixture was stirred for 60 min and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc) to afford 21 as a white solid (4 mg, yield: 74%). MS (ESI): m/z=536 [M+1]. Example 22 methyl 3-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6- (methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)azetidine-1-carboxylate 22

Methyl carbonochloridate (1.2 mg, 0.02 mmol) was added into a solution of 17 (4.5 mg, 0.01 mmol) and DIPEA (2.6 mg, 0.02 mmol) in DCM (3 mL). The mixture was stirred at room temperature overnight, washed with water. The organic phase was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc) to afford 22 as a white solid (3.2 mg, yield: 62%). MS (ESI): m/z=510 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ: 10.93 (s, 1H), 9.26 (s, 1H), 7.99 (s, 1H), 7.98 (s, 1H), 7.78 (br, 1H), 7.77 (d, 1H), 7.75 (d, 1H), 7.21(t, 1H), 4.12 (t, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 3.62 (s, 3H), 3.58 (s, 3H), 2.92-3.00 (m, 4H), 2.80 (d, 2H). Example 23 6-(azetidine-3-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 23

Compound 12 (11mg, 0.02 mmol) was stirred in a mixture of TFA (0.2 mL) and DCM (0.2 mL) for 2 h. The mixture was concentrated in vacuo to afford 23 as a TFA salt (12 mg, yield: 98%). MS (ESI): m/z=438 [M+1]. Example 24 methyl 3-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6- (methylcarbamoyl)pyridazin-3-yl)carbamoyl)azetidine-1-carboxylate 24

To a solution of 23 (15 mg, 0.034 mmol) in DCM (1 mL) was added TEA (10.4 mg, 0.1 mmol) and methyl chloroformate (3.24 mg, 0.034 mmol). After 1h stirring at room temperature, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford 24 as a white solid (5 mg, yield: 29%). MS (ESI): m/z=496 [M+1]. ¹H NMR (400 MHz, CD₃OD) δ: 8.48 (brs, 1H), 8.29 (brs, 1H), 7.69 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.64 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.35-7.30 (m, 1H), 4.20-4.09 (m, 4H), 4.02 (s, 3H), 3.74 (s, 3H), 3.66 (s, 3H), 3.65-3.60 (m, 1H), 2.98 (s, 3H). Example 25 ethyl 3-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6- (methylcarbamoyl)pyridazin-3-yl)carbamoyl)azetidine-1-carboxylate 25

To a solution of 23 (40 mg, 0.11 mmol) in DCM (1 mL) was added TEA (34 mg, 0.34 mmol) and ethyl chloroformate (12.2 mg, 0.11 mmol). After 1h stirring at room temperature, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford 25 as a white solid (20 mg, yield: 35%). MS (ESI): m/z=510 [M+1]. ¹H NMR (400 MHz, DMSO-d₆): δ 11.01 (brs, 1H), 9.20 (brs, 1H), 8.57 (brs, 1H), 8.20 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.33-7.28 (m, 1H), 4.02-3.91 (m, 9H), 3.73 (s, 3H), 3.72-3.64 (m, 1H), 2.86 (s, 3H), 1.14 (t, J = 6.4 Hz, 3H). Example 26 isopropyl 3-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6- (methylcarbamoyl)pyridazin-3-yl)carbamoyl)azetidine-1-carboxylate 26

To a solution of 23 (15 mg, 0.034 mmol) in DCM (1 mL) was added TEA (10 mg, 0.10 mmol) and isopropyl carbonochloridate (4.20 mg, 0.034 mmol). After 1h stirring at room temperature, the mixture was concentrated in vacuo. The residue was purified by prep- HPLC to afford 26 as a white solid (5 mg, yield: 28%). MS (ESI): m/z=524 [M+1]. ¹H NMR (400 MHz, DMSO-d₆): δ 11.16 (brs, 1H), 11.01 (brs, 1H), 9.21-9.18 (m, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 4.76- 4.70 (m, 1H), 4.05-3.92 (m, 3H), 3.95 (s, 3H), 3.73 (s, 3H), 3.71-3.67 (m, 1H), 2.86 (d, J = 4.8 Hz, 3H), 1.15 (d, J = 6.0 Hz, 6H). Example 27 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-(1- pivaloylazetidine-3-carboxamido)pyridazine-3-carboxamide 27

To a solution of 23 (15 mg, 0.034 mmol) in DCM (1 mL) was added TEA (10 mg, 0.10 mmol) and trimethylacetyl chloride (4.20 mg, 0.034 mmol). After 1h stirring at room temperature, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford 27 as a white solid (5 mg, yield: 28%). MS (ESI): m/z=522 [M+1]. ¹H NMR (400 MHz, CD3OD): δ 8.48 (brs, 1H), 8.29 (brs, 1H), 7.69 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.64 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.35-7.31 (m, 1H), 4.62 (br, 2H) , 4.17-4.09 (m, 2H), 4.02 (s, 3H), 3.74 (s, 3H), 3.68-3.64 (m, 1H), 2.98 (s, 3H), 1.20 (s, 9H). Example 28 6-(azetidine-2-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-methylpyridazine-3-carboxamide 28

Compound 13 (12mg, 0.02 mmol) was stirred in a mixture of TFA (0.2 mL) and DCM (0.2 mL) for 2 h. The reaction mixture was concentrated in vacuo to afford 28 as a TFA salt (11 mg, yield: 92%). MS (ESI): m/z=438 [M+1]. ¹H NMR (400 MHz, CD3OD) δ: 8.47 (s, 1H), 8.01 (br, 1H), 7.63 (d, 1H), 7.51 (d, 1H), 7.20 (t, 1H), 5.13 (br, 1H), 4.02-4.08 (m, 1H), 4.03 (s, 3H), 3.91-3.95 (m, 1H), 3.64 (t, 3H), 2.89 (d, 3H), 2.80-2.86 (m, 1H), 2.52-2.58 (m, 1H). BIOLOGICAL ASSAYS The present invention will be further described with reference to the following test examples, but the examples should not be considered as limiting. Test Example 1, KdELECT Competition Binding Assay The KdELECT Competition Binding Assay is performed by a CRO, Eurofins DiscoverX Corporation following the established standard protocol (DiscoverX, San Diego, CA). Briefly, Kinase-tagged T7 phage strains were 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 with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded 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 to reduce nonspecific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17 × PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111-fold stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1 × PBS, 0.05% Tween 20). The beads were then re- suspended in elution buffer (1 × PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by quantitative PCR. Compound Handling: An 11-point 3-fold serial dilution of each test compound was prepared in 100% DMSO at 100-fold final test concentration and subsequently diluted to 1- fold in the assay (final DMSO concentration = 1%). Most Kds were determined using a compound top concentration = 30,000 nM. If the initial Kd determined was < 0.5 nM (the lowest concentration tested), the measurement was repeated with a serial dilution starting at a lower top concentration. A Kd value reported as 40,000 nM indicates that the Kd was determined to be > 30,000 nM. KdELECT Data

Conclusion: The compounds of the present disclosure have a significant inhibition effect on the Tyk2 JH2 Pseudokinase and ligand binding, thus revealing high affinity of compounds to Tyk2 JH2. Test Example 2, IL-23_Kit225 T Cell Assay Kit225 cells (licensed from Professor Toshiyuki Hori, Ritsumeikan University, Japan) were seeded in 384-well plate at a density of 1×10⁵ cells/well in 4 µL Hank's Balanced Salt Solution (HBSS, Gibco), and incubated for 2 hours in a humidified, 5% CO₂ cell culture incubator at 37°C. The cells were treated with serial diluted compounds for 1 hour and stimulated with human recombinant IL-23 (R&D Systems) for 20 minutes. The treated cells were then lysed and cellular phosphorylated-STAT3 levels were measured by AlphaLISA (PerkinElmer) according to the manufacture’s instructions. Inhibition data were calculated by comparison to vehicle control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves were then generated to determine the concentration required to suppress 50% of cellular response (IC₅₀) as derived by non-linear regression analysis using GraphPad Prism. Kit225 T Cell Inhibition Data

62

Conclusion: The compounds of the present disclosure have a significant inhibition effect on the Tyk2-mediated, IL23-induced STAT3 phosphorylation in human Kit225 T cell line. Test Example 3 IFNα_Kit225 T Cell Assay Kit225 cells were seeded in 384-well plate at a density of 0.5 ×10⁵ cells/well in 4 µL HBSS, and incubated for 2 hours in a humidified, 5% CO₂ cell culture incubator at 37°C. The cells were treated with serial diluted compounds for 1 hour and stimulated with human recombinant IFNα (Biolegend) for 20 minutes. The treated cells were then lysed and cellular phosphorylated-STAT1 levels were measured by AlphaLISA (PerkinElmer) according to the manufacture’s instructions. Inhibition data were calculated by comparison to vehicle control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves were then generated to determine the concentration required to suppress 50% of cellular response (IC50) as derived by non-linear regression analysis using GraphPad Prism. IFNα_Kit225 T Cell Inhibition Data

Conclusion: The compounds of the present disclosure have a significant inhibition effect on the Tyk2-mediated, IFNα-induced STAT1 phosphorylation in human Kit225 T cell line. Test Example 4 JAK1 Cellular Selectivity Assay TF-1 cells were seeded in 384-well plate at a density of 0.5 x 10^5 cells/well in 4 µL HBSS, and incubated for 2 hours in a humidified, 5% CO₂ cell culture incubator at 37°C. The cells were treated with serial diluted compounds for 1 hour and stimulated with human recombinant IL6 (Biolegend) for 20 minutes. The treated cells were then lysed and cellular phosphorylated-STAT3 levels were measured by AlphaLISA (PerkinElmer) according to the manufacture’s instructions. Inhibition data were calculated by comparison to vehicle control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves were then generated to determine the concentration required to suppress 50% of cellular response (IC50) as derived by non-linear regression analysis using GraphPad Prism. JAK1 Cell Selectivity Inhibition Data

Conclusion: Compared with BMS986165, the compounds of the present invention have much lower activity in JAK1 specific cell assay. The foregoing embodiments and examples are provided for illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art based on the present disclosure, and such changes and modifications may be made without departure from the spirit and scope of the present invention. All literature cited are incorporated herein by reference in their entireties without admission of them as prior art.

Claims

CLAIMS What is claimed is: 1. A compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

, wherein: G¹ is N or CH; G² and G³ are identical or different, and each is independently selected from the group consisting of NR⁶, CR⁷R⁸, O, S and S(=O)₂; provided that at least one of G¹, G² and G³ is heteroatom; L is a bond or alkylene, wherein the alkylene is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R¹ is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R² and R³ are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; R⁴ at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁵ at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, hydroxyalkyl, -C(O)R⁹, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁷ and R⁸ are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁹ is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R¹⁰ and R¹¹ are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; n is 0 or 1; r is 0, 1, 2, 3, 4 or 5; and t is 0, 1, 2, 3 or 4. 2. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1, wherein ring A is 5 or 6-member heteroaryl. 3. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1, wherein ring A is triazolyl. 4. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 3, wherein L is a bond or CH2. 5. The compound of formula ( I ) according to any one of claims 1 to 4, being a compound of formula ( II ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein: q is 0 or 1; and G¹, G², G³, R¹ to R⁵, n and t are each as defined in claim 1. 6. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 5, wherein

selected from the group consisting of

^{, , and} and G², G³, R⁷ and R⁸ are as

defined in claim 1. 7. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 6, wherein

selected from the group consisting of

O 6 ^{7 8}

and R , R and R are as defined in claim 1. 8. The compound of formula ( I ) according to any one of claims 1 to 7, being a compound of formula ( III ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein: R¹ to R⁵, R⁷ and R⁸ are each as defined in claim 1. 9. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 7, being a compound of formula ( IV ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein: q is 0 or 1; and R¹ to R⁶ are each as defined in claim 1. 10. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 9, wherein R¹ is selected from the group consisting of alkyl, deuterated alkyl and haloalkyl. 11. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 9, wherein R¹ is selected from the group consisting of C_1-6alkyl, deuterated C_1-6alkyl and halo C_1-6alkyl. 12. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 11, wherein R² and R³ are hydrogen. 13. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 12, wherein R⁴ is at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl and hydroxyalkyl. 14. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 12, wherein R⁴ is C_1-6alkoxy. 15. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 14, wherein R⁵ is each identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl and hydroxyalkyl. 16. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 14, wherein R⁵ is C_1-6alkyl. 17. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 7 or 9 to 16, wherein R⁶ is selected from the group consisting of hydrogen, alkyl, haloalkyl, -C(O)R⁹ and -C(O)OR⁹; preferably, R⁶ is - C(O)R⁹ or -C(O)OR⁹; and R⁹ is as defined in claim 1. 18. The compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 8 or 10 to 16, wherein R⁷ and R⁸ are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen and hydroxyl. 19. The compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of:

a

20. A compound of formula ( IA ), or a tautomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein: R^w is alkoxy or hydroxyl; and ring A, G¹, G², G³, L, R² to R⁵, n, r and t are each as defined in claim 1. 21. The compound of formula (IA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 20, wherein the compound is selected from the group consisting of:

22. A process of preparing the compound of formula ( I ) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof comprising a step of:

reacting a compound of formula (IA) with a compound of R¹-NH₂ to obtain the compound of formula ( I ); wherein: R^w is alkoxy or hydroxyl; and ring A, G¹, G², G³, L, R¹ to R⁵, n, r and t are each as defined in claim 1. 23. A pharmaceutical composition comprising a compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 19, and a pharmaceutically acceptable carrier. 24. A method of treating a Tyk2-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula ( I ), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 19, or a pharmaceutical composition according to claim 23. 25. The method of claim 24, wherein the Tyk2-mediated disease or disorder is selected from the group consisting of proliferative diseases, metabolic, allergic, autoimmune and inflammatory diseases or disorders. 26. The method of claim 25, wherein the autoimmune and inflammatory diseases are selected from arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren’s syndrome, systemic scleroderma, ulcerative colitis, Graves’ disease, discoid lupus erythematosus, adult onset stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type I diabetes, insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis, glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyneuropathy(CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy; and the proliferative disease is a cancer.