Amino-substituted heteroaromatic cyclic compound, preparation method therefor and use thereof in medicine

Abstract

The present disclosure relates to an amino-substituted heteroaromatic cyclic compound, a preparation method therefor, and the use thereof in medicine. Specifically, the present disclosure relates to an amino-substituted heteroaromatic cyclic compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, the use thereof as a therapeutic agent, particularly as a TYK2 inhibitor and / or a degradation agent, and the use thereof in the preparation of a drug for treating and / or preventing TYK2-mediated or -dependent diseases or disorders.

Description

Amino-substituted heteroaromatic compounds, processes for their preparation and their use in medicine TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine and relates to a class of amino-substituted heteroaromatic compounds represented by general formula (I), processes for their preparation, pharmaceutical compositions containing the compounds and their use as therapeutic agents, in particular as TYK2 inhibitors and / or degraders and in the manufacture of a medicament for the treatment and / or prevention of diseases or conditions mediated by or dependent on TYK2. BACKGROUND

[0002] Cytokine signaling plays a key role in controlling the growth, differentiation, function and communication of immune cells. Receptor binding Janus kinases (JAKs) and the action of signal transducers and activators of transcription (STATs) mediate a variety of cytokine signaling pathways.

[0003] The JAK family members, including JAK1, JAK2, JAK3 and TYK2, are cytokine receptor-associated non-receptor tyrosine protein kinases that, upon stimulation and oligomerization of these receptors, JAK molecules are activated and phosphorylate receptor tyrosine residues to serve as docking sites for the subsequent STAT protein recruitment and phosphorylation. In turn, the phosphorylated STAT proteins dimerize, translocate to the nucleus and activate the transcription of genes that mediate cytokine-induced responses. These cytokine-mediated JAK / STAT pathways are tightly regulated and dysfunctional JAK / STAT activity has been shown to be a hallmark of many immune and autoimmune diseases, inflammatory diseases and cell transformation.

[0004] Tyrosine kinase 2 (TYK2) is the first member of the JAK family to be identified, a component of various cytokine pathways leading to STAT-dependent gene transcription and specific functional responses of cytokines, including the interleukin 12 / -23 family (IL-12 / IL-23, sharing the p40 subunit), the type I interferon (IFN) family, and the IL-6 and IL-10 families. TYK2-mediated cytokine signaling plays a key role in the pathogenesis of autoimmune and inflammatory diseases. Specifically, IL-23 (a heterodimer containing the p40 and pl9 subunits) is critical for the differentiation and proliferation of T helper 17 (Thl7) cells, which are key players in several autoimmune diseases. IL-12, composed of the p40 and unique p35 subunits, plays an important role in regulating Thl development and IFN-g secretion by these cells. By mediating Thl / Thl7 responses, IL-12 and IL-23 play an important role in various 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). For example, in mouse models, blockade or deletion of the common subunit P40 of IL-12 and IL-23 or the shared receptor IL23R was found to protect mice from various autoimmune diseases (psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, etc.) (Kyttaris VC et al., “Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL / 6-lpr / lpr mice” J Immunol. 2010, 184:4605-9). In human diseases, high levels of IL-12 and IL-23 were observed in the lesional skin of psoriasis patients, which then decreased after various treatments for psoriasis. In addition, monoclonal antibodies that block the IL-12 / IL-23 common subunit p40 (Ustekinumab, Briakinumab, etc.) or the IL-23-specific subunit pl9 (Tildrakizumab, Risankizumab, etc.) have been shown to have clinical efficacy in the treatment of psoriasis, Crohn's disease, etc.Furthermore, type I IFN family members (IFN-α, -β, -ε, -κ, and -ω), which act through heterodimeric IFN receptors (IFNARs), are important mediators of innate and adaptive immunity. They can also activate multiple components of the immune response and enhance the expression and release of autoantigens, making them key players in the amplification of autoimmune diseases. The importance of type I IFNs in the pathogenesis of systemic lupus erythematosus (SLE) has been experimentally confirmed. In the lupus-prone NZB mouse model, IFNAR deficiency significantly reduces disease severity and mortality. In human SLE patients, elevated serum IFNα levels and increased expression of type I IFN-regulated genes in peripheral blood mononuclear cells (PBMCs) and affected organs have been found in many patients. Furthermore, other studies have reported that activation of type I IFNs is closely associated with the severity of SLE disease.

[0005] Multiple studies have demonstrated the importance of TYK2 in the pathogenesis of the aforementioned autoimmune diseases. For example, rodents with inactivated or chemically inhibited TYK2 have been found to exhibit disease resistance in experimental autoimmune disease models such as psoriasis, multiple sclerosis, and inflammatory bowel disease. Population studies have found that children and adults carrying TYK2 loss-of-activity variants (such as rs12720356 and rs34536443) in the Mexican Mestizo population have a reduced incidence of SLE. Furthermore, TYK2 SNP mutations have also been reported to be associated with SLE in Nordic, British, and Han Chinese populations. Genome-wide association studies (GWAS) have found that several loss-of-activity variants in TYK2 are significantly associated with resistance to inflammatory diseases, including multiple sclerosis, psoriasis, Crohn's disease, lupus, and rheumatoid arthritis, further suggesting that TYK2 plays an important role in a wide range of autoimmune diseases.

[0006] Therefore, the development of drugs that inhibit TYK2-mediated cytokine signaling pathways has potential therapeutic benefits for human autoimmune diseases. Indeed, the highly selective allosteric TYK2 inhibitor BMS986165 has been shown to effectively block IL-12 / IL-23 and type I interferon signaling pathways, demonstrating significant efficacy in multiple experimental autoimmune disease models (psoriasis, systemic lupus erythematosus, and inflammatory bowel disease). Furthermore, Phase 2 clinical trial results reported that the drug met its primary efficacy endpoint in patients with moderate to severe plaque psoriasis, with a favorable risk-benefit ratio. After 12 weeks of BMS986165 treatment, most patients achieved a greater than 75% reduction in Psoriasis Area and Severity Index scores (PASI 75), with some achieving a reduction of over 90% (PASI 90), further demonstrating the efficacy and potential of TYK2 as a therapeutic target in autoimmune diseases.

[0007] Patent applications disclosing TYK2 degraders include WO2023076161A1, etc. SUMMARY

[0008] An object of the present disclosure is to provide a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:

[0009] wherein:

[0010] G 1 selected from N, NR 0 , O, S and CR';

[0011] G 2 is N or C;

[0012] G 3 is N or C;

[0013] Z 1 selected from C(O)NR 1 R 2 , C(O)NR 1a OR 2 , C(O)NR 1a NR 1 R 2 , NR 1a C(O)NR 1 R 2 , C(O)C(O)NR 1 R 2 , C(O)R 2 , C(=NR 1a )NR 1 R 2 , S(O) r R 2 , S(=NR 1a )R 2 and S(=NR 1a )(O)R 2 ;

[0014] R 4 , R 5 , R 0 and R 1a are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, OR 12 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; each of the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group is independently optionally substituted with one or more R 01 ;

[0015] R 1 and R 2the same or different, and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 12 , C(O)NR 10 R 11 , C(O)R 10 R 11 , NR 13 C(O)R 12 , C(O)R 12 , C(O)OR 12 , OC(O)R 12 , S(O) r R 12 , S(O) r NR 10 R 11 , a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group, and a heteroaryl group; each of the alkyl group, the alkoxy group, the alkoxyalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the cycloalkylalkyl group, the heterocyclylalkyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more R 01 , R 1 , and R 2 together with the nitrogen atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more R 01 ;

[0016] R 10 , R 11 , R 12 , and R 13 the same or different, and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 21 R 22 , C(O)NR 21 R 22 , NR 23 C(O)R 24 , C(O)R 24 , C(O)OR 24 , OC(O)R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; each of the alkyl group, the alkoxy group, the alkoxyalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more R 01 ;

[0017] or R10 R 11 and the nitrogen atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more R 01 ;

[0018] R 3 R 6 and R' are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, NR 21 R 22 , C(O)NR 21 R 22 , C(O)R 24 , C(O)OR 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , C(=NR 23 )R 24 , S(=NR 23 )R 24 , S(=NR 23 )(O)R 24 , P(O)R 21 R 22 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; each of said alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently optionally substituted with one or more R 02 ;

[0019] L 1 , L 3 , L 4 , L 5 and L 6 are the same or different and each is independently selected from the group consisting of a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C(O), C(O)N(R L ), N(R L )C(O), S(O) r , S(O) r N(R L ), N(R L )S(O) r , N(R L ), S(=NR 23 ), S(=NR 23), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl, and heteroaryl; each of said alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 03 ;

[0020] L 2 is selected from the group consisting of a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl, heteroaryl, and ring B-Z 2 ; each of said alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring B1, and ring B is independently optionally substituted with one or more R 03 ;

[0021] ring B1is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0022] ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0023] Z 2 is selected from the group consisting of a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), alkylene, N(R L ), S(O) r , S(=NR 23 ), S(=NR 23 )(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of said alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 03 ;

[0024] each R 01 , R 02 , R 03 , and R 04 is the same or different, and each is independently selected from the group consisting of oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 21 R 22 , C(O)NR 21 R 22 , NR 23 C(O)R 24 , NR 23 C(O)NR 21 R 22 , C(O)R 24 , C(O)OR24 , OC(O)R 24 , S(O) r R 24 , S(O) r OR 24 , S(O) r NR 21 R 22 , NR 23 S(O) r R 24 , C(=NR 23 )R 24 , S(=NR 23 )R 24 , S(=NR 23 )(O)R 24 , P(O)R 21 R 22 , OR 24 , =CR 15 R 16 , =NR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R * ;

[0025] or two R 03 and the atom to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R * ;

[0026] R 15 and R 16 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 21 R 22 , C(O)NR 21 R 22 , C(O)R 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , cycloalkyl, heterocyclyl, aryl and heteroaryl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R * ; or R 15 , R 16and together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R * substituted;

[0027] R 21 , R 22 , R 23 , R 24 and R L are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, a hydroxy, a hydroxyalkyl, an alkoxyalkyl, an alkenyl, an alkynyl, NR 30 R 31 , C(O)NR 30 R 31 , NR 33 C(O)R 32 , C(O)R 32 , C(O)OR 32 , OC(O)R 32 , OR 32 , S(O) r R 32 , S(O) r NR 30 R 31 , a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl and a heteroarylalkyl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl is independently optionally substituted with one or more R * substituted;

[0028] R 30 , R 31 , R 32 and R 33 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, a hydroxy, a hydroxyalkyl, an alkoxyalkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, a cycloalkylalkyl, a heterocyclylalkyl, an aryl and a heteroaryl;

[0029] E is selected from:

[0030] is a single or double bond;

[0031] Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is a carbon atom and is attached to L 6 , each of the others is independently selected from N, CH and CRq ;

[0032] each R q is the same or different, and each is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 21 R 22 , C(O)NR 21 R 22 , C(O)R 24 , C(O)OR 24 , S(O) r R 24 , S(O) r NR 21 R 22 , OR 24 , C(=NR 23 )R 24 , S(=NR 23 )R 24 , S(=NR 23 )(O)R 24 , P(O)R 21 R 22 , cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 04 ;

[0033] or two R q , together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R 04 ;

[0034] R 7 and R 8 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and heterocyclyl, each of which is independently optionally substituted with one or more R * ;

[0035] Y 1 is N or CR Y1 ;

[0036] Y 2 is CR Y2 R Y4 or C(O);

[0037] Y 3 is N or CR Y3 ;

[0038] RY1 , R Y2 , R Y3 and R Y4 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclyl group; each of said alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclyl group is independently optionally substituted with one or more R * ;

[0039] or, R Y2 , R Y4 and the carbon atom to which they are attached together form a cycloalkyl group or a heterocyclyl group; each of said cycloalkyl group and heterocyclyl group is independently optionally substituted with one or more R * ;

[0040] each R * is the same or different, and each is independently selected from the group consisting of an oxo group, =S, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, a cyano group, an alkenyl group, an alkynyl group, an alkylthio group, an amino group, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, an amido group, a nitro group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, an aryl group, and a heteroaryl group;

[0041] each r is the same or different, and each is independently 0, 1, or 2.

[0042] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

[0043] wherein E, L 1 to L 6 , Z 1 and R 3 to R 6 are as defined in the general formula (I).

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

[0045] wherein E, L 1 to L 6 , Z 1 and R 3 to R 6 are as defined in the general formula (I).

[0046] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof,

[0047] Where s is 0, 1, 2 or 3;

[0048] Z 1 , L 1 To L 6 、R 3 to R 7 and R q As defined in general formula (I).

[0049] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V), (V-1) or (V-2) or a pharmaceutically acceptable salt thereof,

[0050] Where s is 0, 1, 2 or 3;

[0051] L 1 To L 6 、R 1a 、R 1 to R 7 and R q As defined in general formula (I).

[0052] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein Z 1 C(O)NR 1a NR 1 R 2 In some embodiments, Z 1 NR 1a C(O)NR 1 R 2 In some embodiments, Z 1 C(O)NR 1 R 2 In some embodiments, Z 1 C(O)R 2 ; R 1a 、R 1 and R 2 As defined in formula (I); in some embodiments, Z 1 Selected from

[0053] In some embodiments of the disclosure, the compound of Formula (I)-(V) or a pharmaceutically acceptable salt thereof, wherein E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: s is 0, 1, 2, or 3, s1 is 0, 1, 2, 3, or 4, R q , R 7 , R 8 , Y 1 , and Y 2 are as defined in Formula (I);

[0054] In some embodiments, E is selected from: In some embodiments, E is selected from: In some embodiments, E is selected from: s is 0, 1, 2, or 3, R q , and R 7 are as defined in Formula (I); in some embodiments, E is selected from In some embodiments, E is selected from

[0055] In some embodiments of the disclosure, the compound of Formula (I)-(V) or a pharmaceutically acceptable salt thereof, wherein is In some embodiments is In some embodiments is R q , R 7 , and s are as defined in Formula (I).

[0056] In some embodiments of the disclosure, the compound of Formula (I)-(V) or a pharmaceutically acceptable salt thereof, wherein is In some embodiments is In some embodiments is R q , R 7 , and s are as defined in Formula (I).

[0057] In some embodiments of the disclosure, the compound of Formula (I)-(V) or a pharmaceutically acceptable salt thereof, wherein For In some embodiments is In some embodiments is R q , R 7 and s are as defined in general formula (I).

[0058] In some embodiments of the present disclosure, the compounds of general formulae (I) to (V), or pharmaceutically acceptable salts thereof, wherein R 1a is selected from the group consisting of a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a 3- to 6-membered cycloalkyl group and OR 12 , R 12 are as defined in general formula (I); in some embodiments, R 1a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C 1-6 alkoxy group; in some embodiments, R 1a is a hydrogen atom.

[0059] In some embodiments of the present disclosure, the compounds of general formulae (I) to (V), or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered cycloalkyl C 1-6 alkyl group and a 3- to 6-membered heterocyclyl group, each of said C 1-6 alkyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered cycloalkyl C 1-6 alkyl group and 3- to 6-membered heterocyclyl group being independently optionally substituted with one or more R 01 ; or R 1 , R 2 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclyl group, said 3- to 6-membered heterocyclyl group being optionally substituted with one or more R 01 ;

[0060] In some embodiments, R 1 is a hydrogen atom or a C 1-6 alkyl group, R 2 is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group and a 3- to 6-membered heterocyclyl group, each of said 3- to 6-membered cycloalkyl group and 3- to 6-membered heterocyclyl group being independently optionally substituted with one or more R 01 ; or R 1 , R 2 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclyl group, said 3- to 6-membered heterocyclyl group being optionally substituted with one or more R 01 ; R 01 is as defined in general formula (I).

[0061] In some embodiments, R 1 C 1-6 Alkyl, R 2 C 1-6 Alkyl, or R 1 、R 2 Together with the nitrogen atom to which it is attached, it forms a ring The rings are each independently optionally selected from halogen, C 1-6 Alkyl and =CR 15 R 16 is substituted by one or more of 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;

[0062] In some embodiments, R 1 C 1-6 Alkyl, R 2 C 1-6 Alkyl, or R 1 、R 2 Together with the nitrogen atom to which it is attached,

[0063] In some embodiments, R 1 、R 2 and the nitrogen atom to which it is attached together form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted by one or more R 01 Replaced by; R 01 As defined in formula (I);

[0064] In some embodiments, R 1 、R 2 Together with the nitrogen atom to which it is attached, it forms a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted with one or more ═CR 15 R 16 Replaced by; R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen;

[0065] In some embodiments, R 1 、R 2 Together with the nitrogen atom to which it is attached, which are each independently optionally selected from halogen, C 1-6 Alkyl and =CR 15 R 16 is substituted by one or more of 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 1 、R2 and the nitrogen atom to which it is attached form

[0066] In some embodiments of the disclosure, the compound of Formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered cycloalkyl C 1-6 alkyl and 3- to 10-membered heterocyclyl C 1-6 alkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered cycloalkyl C 1-6 alkyl and 3- to 10-membered heterocyclyl C 1-6 each independently optionally substituted with one or more R 01 is as defined in Formula (I); in some embodiments, R 01 is as defined in Formula (I); in some embodiments, R 1 is selected from a hydrogen atom, C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 alkyl; in some embodiments, R 1 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 1 is selected from a hydrogen atom, methyl and ethyl; in some embodiments, R 1 is a hydrogen atom; in some embodiments, R 1 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 1 is ethyl.

[0067] In some embodiments of the disclosure, the compound of Formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, OR 12, NR 10 R 11 , OC(O)R 12 , 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered cycloalkyl C 1-6 alkyl and 3- to 10-membered heterocyclyl C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered cycloalkyl C 1-6 alkyl and 3- to 10-membered heterocyclyl C 1-6 each independently optionally substituted by one or more R 01 , or R 2 , R 1 and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclyl group optionally substituted by one or more R 01 ; R 01 , R 10 , R 11 and R 12 are as defined in general formula (I);

[0068] In some embodiments, R 2 is selected from a hydrogen atom, C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, each independently optionally substituted by one or more of oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy and =CR 15 R 16 R 15 and R 16 are the same or different and each independently a hydrogen atom or halogen, or R 2 , R 1 and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclyl group optionally substituted by one or more R 01 ;

[0069] In some embodiments, R 2 is C 1-6 alkyl or 3- to 6-membered heterocyclyl optionally substituted by one or more of halogen, C 1-6 alkoxy, hydroxy and =CR 15 R 16 R 15 and R 16 are the same or different and each independently a hydrogen atom or halogen;

[0070] In some embodiments, R2 C 1-6 alkyl, or R 2 , R 1 and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted with one or more R 01 C 2 alkyl; 1-6 alkyl;

[0071] In some embodiments, R 2 is selected from ethyl, In some embodiments, R 2 is selected from ethyl, In some embodiments, R 2 is selected from ethyl, In some embodiments, R 2 is selected from In some embodiments is

[0072] In some embodiments of the disclosure, the compounds of general formula (I) to (V), or pharmaceutically acceptable salts thereof, wherein L 1 is selected from bond, O, S, O-C 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl-C(O), C(O)N(R L ), N(R L )C(O), N(R L ), S(=NR 23 ), S(=NR 23 )(O), C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl; each of said C 1- 6alkylene, C 2-6 alkenylene, C 2-6 alkynylene, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl is independently optionally substituted with one or more R 03 .L and R 03 as defined in general formula (I);

[0073] In some embodiments, L 1 is a bond or N(R L ); in some embodiments, L 1 is N(R L ), R L as defined in general formula (I); in some embodiments, L 1 is N(R L ), R L is a hydrogen atom or C 1-6 alkyl; in some embodiments, L 1 is a bond or NH; in some embodiments, L 1 is NH.

[0074] In some embodiments of the present disclosure, the compounds of general formulae (I) to (V), or pharmaceutically acceptable salts thereof, wherein L 2 is selected from a bond, C(O), O, S, C 1-6 alkylene, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, ring B - 6- to 14-membered aryl, ring B - 5- to 14-membered heteroaryl, and the C 1-6 alkylene, 3- to 12-membered heterocyclyl, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, and ring B are each independently optionally substituted with one or more R 03 ;

[0075] In some embodiments, L 2 is selected from 6- to 14-membered aryl, 5- to 14-membered heteroaryl, phenyl-ring B, and the 6- to 14-membered aryl, 5- to 14-membered heteroaryl, phenyl, and ring B are each independently optionally substituted with one or more R 03 ; 03 as defined in general formula (I);

[0076] In some embodiments, L 2 is In some embodiments, L 2 is b is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; ring B, Z 2 and R 03 as defined in general formula (I);

[0077] In some embodiments, L 2 is selected from Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring C is a nitrogen-containing heterocyclyl or heteroaryl; m is 0, 1, 2, 3, 4, 5, or 6; t is an integer from 0 to 16; in some embodiments, L 2 is selected from the group consisting of Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring E is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; W is selected from the group consisting of CH, C, and N; J 1 and J 2 are the same or different and each is independently selected from the group consisting of a bond, (CR a R b ) q , (CR a R b ) q O, O(CR a R b ) q , NR i , O, and S; R a and R b are the same or different and each is independently a hydrogen atom or R 03 ; R i is a hydrogen atom or alkyl; R e , R f , and the carbon atom to which they are attached together form a cycloalkyl or heterocyclyl group, R j and R k are a hydrogen atom or R 03 , or R j , R k , and the carbon atom to which they are attached together form a cycloalkyl or heterocyclyl group, R e and R f are a hydrogen atom or R 03 , L 2 is attached to the formed ring or to J 1 or J 2 ; m is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, or 2; b is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; Ring B and R 03 are as defined in General Formula (I);

[0078] in some embodiments, L 2 is selected from the group consisting of in some embodiments, L 2 is selected from the group consisting of in some embodiments, L 2 is u is 1, 2, 3, or 4; Q and L are the same or different and each is independently selected from the group consisting of a bond, (CRg R h ) q , (CR g R h ) q O, O(CR g R h ) q , NR i , O and S; R g and R h are the same or different and each independently a hydrogen atom or R 03 ; R i is a hydrogen atom or an alkyl group; n is 0, 1, 2 or 3; b is 0, 1, 2 or 3; a is 0, 1 or 2; q is 0, 1 or 2; R 03 are as defined in general formula (I);

[0079] In some embodiments, L 2 is selected from In some embodiments, L 2 is selected from

[0080] In some embodiments, L 2 is selected from is the point of attachment to L 1 and L 3 .

[0081] In some embodiments of the disclosure, the compounds of general formula (I) to (V), or pharmaceutically acceptable salts thereof, wherein ring B1 is

[0082] In some embodiments of the disclosure, the compounds of general formula (I) to (V), or pharmaceutically acceptable salts thereof, wherein Z 2 is a bond or a 3- to 10-membered heterocyclyl group optionally substituted with one or more R 03 ; in some embodiments, Z 2 is a bond; in some embodiments, Z 2 is a 3- to 10-membered heterocyclyl group optionally substituted with one or more R 03 ; in some embodiments, Z 2 is a 3- to 6-membered heterocyclyl group optionally substituted with one or more R 03 ; R 03 are as defined in general formula (I).

[0083] In some embodiments of the disclosure, the compound of Formula (I)-(V), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 3-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; in some embodiments, ring B is selected from 3-10 membered heterocyclyl, phenyl, 5 or 6 membered heteroaryl, and 9 or 10 membered heteroaryl; in some embodiments, ring B is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, and pyrimidinyl; in some embodiments, ring B is pyridyl; in some embodiments, ring B is In some embodiments of the above, ring B is optionally substituted with one or more R 03 as defined in Formula (I). 03 as defined in Formula (I).

[0084] In some embodiments of the disclosure, ring A is 3-12 membered cycloalkyl or 3-12 membered heterocyclyl; in some embodiments, ring A is 3-12 membered heterocyclyl; in some embodiments, ring A is 7-12 membered heterocyclyl; in some embodiments, ring A is 7-12 membered bicyclic heterocyclyl; in some embodiments, ring A is 7, 8, or 9 membered bicyclic heterocyclyl; in some embodiments, ring A is selected from In some embodiments, ring A is selected from is a site of fusion.

[0085] In some embodiments of the disclosure, ring C is 7-12 membered nitrogen-containing heterocyclyl; in some embodiments, ring C is 8, 9, or 10 membered bicyclic nitrogen-containing heterocyclyl.

[0086] In some embodiments of the disclosure, ring E is aryl or heteroaryl; in some embodiments, ring E is selected from phenyl, 5 or 6 membered heteroaryl, 3-8 membered cycloalkyl, and 3-8 membered heterocyclyl; in some embodiments, ring E is phenyl or 6 membered heteroaryl; in some embodiments, ring E is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, and pyrimidinyl; in some embodiments, ring E is pyridyl; in some embodiments, ring E is is a site of fusion.

[0087] In some embodiments of the disclosure, the compound of Formula (I)-(V), or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from bond, O, S, O-C 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3-12 membered heterocyclyl, 3-12 membered heterocyclyl-C(O), C(O)N(R L ), N(R L)C(O), S(O) r r N(R L )S(O) L )S(O) r L )S(O) 23 )S(O) 23 )S(O) 1- 6alkylene, C 2-6 alkenylene, C 2-6 alkynylene, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, C 1-6 alkylene-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl-C 1-6 alkylene, 3- to 12-membered heterocyclyl-3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl; each of said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 14-membered aryl, and 5- to 14-membered heteroaryl is independently optionally substituted with one or more R 03 , R L , and R 03 are as defined in general formula (I); in some embodiments, L 3 is selected from a bond, C 1-6 alkylene, and 3- to 12-membered heterocyclyl optionally substituted with one or more R 03 ; R 03 is as defined in general formula (I); in some embodiments, L 3 is a bond or C 1-6 alkylene; in some embodiments, L 3 is a bond or (CH2) p , p is 0, 1, 2, 3, or 4; in some embodiments, L 3 is a bond.

[0088] In some embodiments of the disclosure, the compounds of general formulae (I) to (V), or pharmaceutically acceptable salts thereof, wherein L 4 is selected from a bond, O, S, O-C 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl-C(O), C(O)N(R L )S(O) L )S(O) r , S(O)​​r N(R L )、N(R L )S(O) r 、N(R L ), S(=NR 23 ), S(=NR 23 )(O), C 1- 6 alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, C 1-6 alkylene-3 to 12 membered heterocyclic group, 3 to 12 membered heterocyclic group-C 1-6 Alkylene, 3 to 12 membered heterocyclyl-3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 14 membered heteroaryl; the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 14 membered aryl and 5 to 14 membered heteroaryl are each independently optionally substituted with one or more R 03 Replaced by r, R L and R 03 As defined in formula (I); in some embodiments, L 4 Selected from bond, C 1-6 Alkylene, C(O) and 3 to 12 membered heterocyclic group, said 3 to 12 membered heterocyclic group being optionally substituted by one or more R 03 Replaced by; R 03 As defined in formula (I); in some embodiments, L 4 selected from C(O), 3- to 12-membered heterocyclyl-C(O), C(O)N(R L ) and C 1-6 Alkylene, the 3 to 12 membered heterocyclic group is optionally replaced by one or more R 03 Replaced by; R L and R 03 As defined in formula (I); in some embodiments, L 4 C 1-6 alkylene or C(O); in some embodiments, L 4 (CH2) p or C(O), p is 0, 1, 2, 3 or 4; in some embodiments, L 4 is C(O); in some embodiments, L 4 for or C(O); in some embodiments, L 4 for

[0089] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein L 5 Selected from bond, O, S, OC 1-6 Alkylene, C 1-6 Alkylene-O, C(O), C(O)-C 1-6 Alkylene, C 1-6 Alkylene-C(O), C(O)-3 to 12-membered heterocyclyl, 3 to 12-membered heterocyclyl-C(O), C(O)N(R L )、N(R L )C(O), S(O) r 、S(O) r N(R L )、N(R L )S(O) r 、N(R L ), S(=NR 23 ), S(=NR 23 )(O), C 1- 6 alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, C 1-6 alkylene-3 to 12 membered heterocyclic group, 3 to 12 membered heterocyclic group-C 1-6 Alkylene, 3 to 12 membered heterocyclyl-3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 14 membered heteroaryl; the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 14 membered aryl and 5 to 14 membered heteroaryl are each independently optionally substituted with one or more R 03 Replaced by r, R L and R 03 As defined in formula (I); in some embodiments, L 5 is a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group is optionally substituted by one or more R 03 In some embodiments, L 5 is a 3- to 12-membered heterocyclyl; in some embodiments, L 5 for U is selected from N, CH and CR 03 , V is selected from N, CH and CR 03 ; c is 0, 1 or 2; d is 0, 1 or 2; e is 0, 1 or 2; f is 1 or 2; v is 0, 1, 2, 3 or 4; R 03 As defined in formula (I); in some embodiments, L 5 for

[0090] In some embodiments of the disclosure, the compounds of Formula (I)-(V), or pharmaceutically acceptable salts thereof, are those wherein L 6 is selected from the group consisting of a bond, O, S, O-C 1-6 alkylene, C 1-6 alkylene-O, C(O), C(O)-C 1-6 alkylene, C 1-6 alkylene-C(O), C(O)-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl-C(O), C(O)N(R L ), N(R L )C(O), S(O) r , S(O) r N(R L ), N(R L )S(O) r , N(R L ), S(=NR 23 ), S(=NR 23 )(O), C 1- 6alkylene, C 2-6 alkenylene, C 2-6 alkynylene, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 14-membered aryl, and 5- to 14-membered heteroaryl; each of said C 1-6 alkylene-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl-C 1-6 alkylene, 3- to 12-membered heterocyclyl-3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl; each of said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 14-membered aryl, and 5- to 14-membered heteroaryl is independently optionally substituted with one or more R 03 , R L , and R 03 are as defined in Formula (I); in some embodiments, L 6 is selected from the group consisting of a bond, C 1-6 alkylene, and 3- to 12-membered heterocyclyl optionally substituted with one or more R 03 ; R 03 are as defined in Formula (I); in some embodiments, L 6 is a bond.

[0091] In some embodiments of the disclosure, the compounds of Formula (I)-(V), or pharmaceutically acceptable salts thereof, are those wherein L 6 -L 5 -L 4 -L 3C(O)-3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl-C(O), 3 to 12 membered heterocyclyl-C 1-6 alkylene and C 1-6 alkylene-3 to 12 membered heterocyclyl, said 3 to 12 membered heterocyclyl being optionally substituted with one or more R 03 ; in some embodiments, L 6 -L 5 -L 4 -L 3 is heterocyclyl-C(O) or heterocyclyl-C 1-6 alkylene, said heterocyclyl being optionally substituted with one or more R 03 ; in some embodiments, L 6 -L 5 -L 4 -L 3 is 3 to 12 membered heterocyclyl-C(O) or 3 to 12 membered heterocyclyl-C 1-6 alkylene, said 3 to 12 membered heterocyclyl being optionally substituted with one or more R 03 ; in some embodiments, L 6 -L 5 -L 4 -L 3 is 3 to 12 membered heterocyclyl-C(O), said 3 to 12 membered heterocyclyl being optionally substituted with one or more R 03 ; in some embodiments, L 03 is as defined in general formula (I);

[0092] ; in some embodiments, L 6 -L 5 -L 4 -L 3 is selected from ; in some embodiments, L 6 -L 5 -L 4 -L 3 is U is selected from N, CH and CR 03 ; V is selected from N, CH and CR 03 ; T is selected from N, CH and CR 03 ; W is selected from N, CH and CR 03 ; c is 0, 1 or 2; d is 0, 1 or 2; e is 0, 1 or 2; f is 1 or 2; v is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3 or 4, R 03 is as defined in general formula (I);

[0093] ; in some embodiments, L 6 -L5 -L 4 -L 3 is In some embodiments, L 6 -L 5 -L 4 -L 3 is In some embodiments, L 6 -L 5 -L 4 -L 3 is selected from In some embodiments is

[0094] In some embodiments of the disclosure, the compound of Formula (I) to (V) or pharmaceutically acceptable salt thereof, wherein is selected from

[0095] In some embodiments, is selected from

[0096] In some embodiments, is

[0097] In some embodiments of the disclosure, U is CH or N, and / or V is CH or N.

[0098] In some embodiments of the disclosure, U is CH or N, and / or V is CH or N, and c is 1, and / or d is 0 or 1, and / or e is 1, and / or f is 1 or 2.

[0099] In some embodiments of the disclosure, v is 0, 1 or 2; in some embodiments, v is 0.

[0100] In some embodiments of the disclosure, T is CH or N, and / or W is CH or N.

[0101] In some embodiments of the disclosure, Q is selected from a bond, O, CH2O and CH2CH2O, and / or L is selected from a bond, O, CH2O and CH2CH2O; in some embodiments, Q is selected from a bond, O, CH2O and CH2CH2O, and / or L is a bond or O; in some embodiments, Q is a bond or O, and / or L is a bond or O; in some embodiments, Q is O, and / or L is O.

[0102] In some embodiments of the disclosure, u is 1 or 2; in some embodiments, u is 1.

[0103] In some embodiments of the disclosure, Q is a bond or O, and / or L is a bond or O, and / or u is 1 or 2; in some embodiments, Q is O, and / or L is O, and / or u is 1.

[0104] In some embodiments of the disclosure, a is 0, 1, or 2; in some embodiments, a is 1.

[0105] In some embodiments of the disclosure, b is 0, 1, or 2; in some embodiments, b is 0.

[0106] In some embodiments of the disclosure, n is 0, 1, or 2; in some embodiments, n is 0.

[0107] In some embodiments of the disclosure, p is 0, 1, or 2; in some embodiments, p is 1.

[0108] In some embodiments of the disclosure, t is 0, 1, or 2; in some embodiments, t is 0.

[0109] In some embodiments of the disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein is In some embodiments, is In some embodiments, is

[0110] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; in some embodiments, R 3 is a hydrogen atom.

[0111] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 4 is a hydrogen atom.

[0112] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from a hydrogen atom, C 1-6 alkyl, and 3- to 6-membered cycloalkyl; in some embodiments, R 5 is a hydrogen atom or C1-6 alkyl; in some embodiments, R 5 is C 1-6 alkyl; in some embodiments, R 5 is methyl.

[0113] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; in some embodiments, R 6 is a hydrogen atom.

[0114] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, and / or R 6 is a hydrogen atom.

[0115] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom, and / or R 5 is C 1-6 alkyl; in some embodiments, R 4 is a hydrogen atom, and / or R 5 is methyl.

[0116] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, and / or R 6 is a hydrogen atom, and / or R 4 is a hydrogen atom, and / or R 5 is C 1-6 alkyl; in some embodiments, R 3 is a hydrogen atom, and / or R 6 is a hydrogen atom, and / or R 4 is a hydrogen atom, and / or R 5 is methyl.

[0117] In some embodiments of the disclosure, the compound of Formula (I) to (V) or a pharmaceutically acceptable salt thereof, wherein R L is a hydrogen atom or C 1-6 alkyl; in some embodiments, R L is a hydrogen atom.

[0118] In some embodiments of the present disclosure, the compounds of Formulae (I) to (V), or pharmaceutically acceptable salts thereof, are provided, wherein each R 01 are the same or different and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyalkyl, 3- to 6-membered cycloalkyl, and =CR 15 R 16 , R 15 and R 16 are as defined in Formula (I); in some embodiments, each R 01 are the same or different and each is independently selected from oxo, halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, 3- to 6-membered cycloalkyl, and =CR 15 R 16 , R 15 and R 16 are the same or different and each is independently a hydrogen atom, halo, and C 1-6 alkyl; in some embodiments, each R 01 are the same or different and each is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, and =CR 15 R 16 , R 15 and R 16 are the same or different and each is independently a hydrogen atom or halo; in some embodiments, each R 01 are the same or different and each is independently selected from oxo, F, methyl, methoxy, hydroxyl, cyclopropyl, In some embodiments, each R 01 are the same or different and each is independently selected from F, methyl, methoxy, and In some embodiments, each R 01 are the same or different and each is independently =CR 15 R 16 ; R 15 and R 16 are as defined in Formula (I); in some embodiments, each R 01 are the same or different and each is independently =CR 15 R 16 ; R 15 and R 16 are the same or different and each is independently a hydrogen atom or halo; in some embodiments, R 01 is

[0119] In some embodiments of the disclosure, the compound of Formula (I)-(V), or pharmaceutically acceptable salt thereof, wherein each R 02 are the same or different and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3- to 6-membered cycloalkyl; in some embodiments, each R 02 are the same or different and each is independently selected from halo, C 1-6 alkyl and C 1-6 haloalkyl.

[0120] In some embodiments of the disclosure, the compound of Formula (I)-(V), or pharmaceutically acceptable salt thereof, wherein each R 03 are the same or different and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl and 3- to 6-membered cycloalkyl, or two R 03 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; in some embodiments, each R 03 are the same or different and each is independently selected from halo, C 1-6 alkyl and C 1-6 haloalkyl, or two R 03 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; in some embodiments, each R 03 are the same or different and each is independently selected from halo, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, each R 03 are the same or different and each is independently halo; in some embodiments, R 03 is F.

[0121] In some embodiments of the disclosure, the compound of Formula (I)-(V), or pharmaceutically acceptable salt thereof, wherein each R 04 are the same or different and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 04 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0122] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R * are the same or different and are each independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R * are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0123] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 10 and R 11 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 10 and R 11 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 10 and R 11 All are hydrogen atoms.

[0124] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 12 Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 12 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 12 is a hydrogen atom; in some embodiments, R 12 C 1-6 alkyl.

[0125] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 15 and R 16the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R 15 and R 16 the same or different, and each independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 the same or different, and each independently a hydrogen atom or F; in some embodiments, R 15 and R 16 are both F.

[0126] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 21 and R 22 the same or different, and each independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 21 and R 22 are both hydrogen atoms.

[0127] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 23 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 23 is a hydrogen atom.

[0128] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 24 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 24 is a hydrogen atom; in some embodiments, R 24 is C 1-6 alkyl.

[0129] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein r is 2; in some embodiments, r is 1; in some embodiments, r is 0.

[0130] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 30 and R 31 the same or different, and each independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 30 and R 31 are both hydrogen atoms.

[0131] In some embodiments of the disclosure, the compound of Formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 32 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 32 is a C 1-6 alkyl group.

[0132] In some embodiments of the disclosure, the compound of Formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 33 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 33 is a hydrogen atom.

[0133] In some embodiments of the disclosure, the compound of Formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from a hydrogen atom, C 1-6 alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 7 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 7 is a C 1-6 alkyl group; in some embodiments, R 7 is a methyl group.

[0134] In some embodiments of the disclosure, the compound of Formula (I) to (V), or a pharmaceutically acceptable salt thereof, wherein R 8 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 8 is a hydrogen atom.

[0135] In some embodiments of the disclosure, the compound of Formula (I) to (III), or a pharmaceutically acceptable salt thereof, wherein Y 1 is N or CH; in some embodiments, Y 1 is N; in some embodiments, Y 1 is CH.

[0136] In some embodiments of the disclosure, the compound of Formula (I) to (III), or a pharmaceutically acceptable salt thereof, wherein Y 2 is CH2or C(O); in some embodiments, Y 2 is CH2; in some embodiments, Y 2 is C(O).

[0137] In some embodiments of the disclosure, the compound of Formula (I) to (III), or a pharmaceutically acceptable salt thereof, wherein Y 3 is N or CH; in some embodiments, Y 3is CH.

[0138] In some embodiments of the disclosure, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein each R q are the same or different and each is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, each R q are the same or different and each is independently selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, each R q are the same or different and each is independently halogen; in some embodiments, R q is F.

[0139] In some embodiments of the disclosure, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein each R q are the same or different and each is independently selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl, and / or s is 0, 1, or 2; in some embodiments, each R q are the same or different and each is independently halogen, and / or s is 0, 1, or 2.

[0140] In some embodiments of the disclosure, R a and R b are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R a and R b are both hydrogen atoms.

[0141] In some embodiments of the disclosure, R i is a hydrogen atom or C 1-6 alkyl; in some embodiments, R i is a hydrogen atom.

[0142] In some embodiments of the disclosure, J 1 is selected from the group consisting of a bond, CH2, CH2CH2, CH2O, OCH2, and O, and / or J 2 is selected from the group consisting of a bond, CH2, CH2CH2, CH2O, OCH2, and O; in some embodiments, J 1 is selected from the group consisting of a bond, O, CH2, and CH2CH2, and / or J 2is O or CH2O; in some embodiments, J 1 is CH2, and / or J 2 is O or CH2O; in some embodiments, J 1 is CH2, and / or J 2 is O.

[0143] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is C 1-6 alkyl; Z 1 is C(O)NR 1a NR 1 R 2 , R 1a is a hydrogen atom, R 1 is a hydrogen atom or C 1-6 alkyl, R 2 is selected from a group consisting of a hydrogen atom, C 1-6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is independently optionally substituted with one or more R 01 , or R 1 , R 2 and the nitrogen atom to which they are attached together form a 3- to 6-membered heterocyclyl group, which is optionally substituted with one or more R 01 ; each R 01 is the same or different, and each is independently selected from a group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, and =CR 15 R 16 , R 15 and R 16 are the same or different, and each is independently a hydrogen atom or halogen;

[0144] E is selected from: s is 0, 1, 2, or 3, R 7 is a hydrogen atom or C 1-6 alkyl; R 8 is a hydrogen atom; Y 1 is N or CH; Y 2 is CH2or C(O); each R q is the same or different, and each is independently halogen; L 6 -L 5 -L 4 -L 3 is 3- to 12-membered heterocyclyl-C(O) or 3- to 12-membered heterocyclyl-C1-6 Alkylene, the 3 to 12 membered heterocyclic group is optionally replaced by one or more R 03 Replaced by; L 2 Selected from Q is 0, L is 0; u is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; n is 0, 1 or 2; each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; L 1 For NH.

[0145] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is methyl; Z 1 C(O)NR 1a NR 1 R 2 , R 1a is a hydrogen atom, R 1 C 1-6 Alkyl, R 2 C 1-6 Alkyl, or R 1 、R 2 Together with the nitrogen atom to which it is attached,

[0146] E is selected from: s is 0, 1, or 2, R 7 is methyl; R 8 is a hydrogen atom; Y 1 N or CH; Y 2 is CH2 or C(O); each R q The same or different, and each independently F; L 6 -L 5 -L 4 -L 3 for L 2 Selected from Q is 0, L is 0; u is 1 or 2; a is 1; b is 0; n is 0; each R 03 are the same or different and are each independently halogen; L 1 For NH.

[0147] In some embodiments of the present disclosure, the compound represented by the general formula (V), (V-1), (V-2) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a C 1-6 alkyl group; R 1a is a hydrogen atom, R 1 is a hydrogen atom or a C 1-6 alkyl group, R 2 is selected from a group consisting of a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group and a 3- to 6-membered heterocyclic group, each of which is independently optionally substituted with one or more R 01 , or R 1 , R 2 and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic group, which is optionally substituted with one or more R 01 ; each R 01 is the same or different, and each is independently selected from a group consisting of a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a hydroxyl group and =CR 15 R 16 , R 15 and R 16 are the same or different, and each is independently a hydrogen atom or a halogen;

[0148] s is 0, 1, 2 or 3, R 7 is a hydrogen atom or a C 1-6 alkyl group; each R q is the same or different, and each is independently selected from a group consisting of a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; L 6 is -L 5 is -L 4 is -L 3 is a 3- to 12-membered heterocyclic group-C(O) or a 3- to 12-membered heterocyclic group-C 1-6 alkylene group, which is optionally substituted with one or more R 03 ; L 2 is selected from Q is O, L is O; u is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; n is 0, 1 or 2; each R 03 is the same or different, and each is independently selected from a group consisting of a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; L 1 is NH.

[0149] In some embodiments of the disclosure, the compound represented by the general formula (V), (V-1), (V-2) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a C 1-6 alkyl group; R 1a is a hydrogen atom, R 1 is a C 1-6 alkyl group, R 2 is a C 1-6 alkyl group, or R 1 , R 2 and the nitrogen atom to which they are attached form s is 0, 1, 2 or 3, R 7 is a methyl group; each R q is the same or different, and each is independently a halogen; L 6 -L 5 -L 4 -L 3 is L 2 is b is 0, 1 or 2; n is 0, 1 or 2; each R 03 is the same or different, and each is independently a halogen; L 1 is NH.

[0150] In some embodiments of the disclosure, the compound represented by the general formula (IV), (IV-1), (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, R 6 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a methyl group; Z 1 is C(O)NR 1 R 2 ; R 1 is a hydrogen atom; R 2 is selected from

[0151] is is is R 7 is a methyl group; each R q is the same or different, and each is independently a halogen, s is 0, 1 or 2; is selected from

[0152] Table A representative compounds of the disclosure include, but are not limited to:

[0153] Another aspect of the present disclosure provides a compound represented by general formula (IA) or a salt thereof,

[0154] Among them, R P is an amino protecting group, preferably PMB;

[0155] Z 1 , G 1 , G 2 , G 3 , L 1 To L 6 , E, R 3 、R 5 and R 6 As defined in general formula (I).

[0156] Another aspect of the present disclosure provides a compound represented by general formula (IIA) or a salt thereof,

[0157] Among them, R P is an amino protecting group, preferably PMB;

[0158] Z 1 , E, L 1 To L 6 、R 3 、R 5 and R 6 As defined in general formula (II).

[0159] Another aspect of the present disclosure provides a compound represented by general formula (IIIA) or a salt thereof,

[0160] Among them, R P is an amino protecting group, preferably PMB;

[0161] Z 1 , E, L 1 To L 6 、R 3 、R 5 and R 6 As defined in general formula (III).

[0162] Another aspect of the present disclosure provides a compound represented by general formula (IVA), (IV-1A) or (IV-2A) or a salt thereof,

[0163] Among them, R P is an amino protecting group, preferably PMB;

[0164] Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in general formula (IV), (IV-1) or (IV-2).

[0165] Another aspect of the present disclosure provides a compound represented by general formula (V), (V-1A) or (V-2A), or a salt thereof,

[0166] wherein, R P is an amino protecting group, preferably PMB;

[0167] R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in general formula (V), (V-1) or (V-2).

[0168] Typical intermediate compounds of the present disclosure or a salt thereof include, but are not limited to, those shown in Table B:

[0169] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0170] The compound represented by general formula (IA) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

[0171] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0172] Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5and R 6 as defined in general formula (I).

[0173] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0174] deprotecting a compound represented by general formula (IIA) or a salt thereof to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0175] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0176] Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 as defined in general formula (II).

[0177] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0178] deprotecting a compound represented by general formula (IIIA) or a salt thereof to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

[0179] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0180] Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 as defined in general formula (III).

[0181] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IV), (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0182] deprotecting a compound represented by general formula (IVA) or a salt thereof to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof;

[0183] The compound represented by General Formula (IV-1A) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (IV-1) or a pharmaceutically acceptable salt thereof;

[0184] The compound represented by General Formula (IV-2) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0185] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0186] Z 1 , R 3 , R 5 , R 6 , R 1 , L 6 to L 7 , R q , R q and s are as defined in General Formula (IV), (IV-1) or (IV-2).

[0187] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formulae (V), (V-1) and (V-2) above or a pharmaceutically acceptable salt thereof, the method comprising:

[0188] The compound represented by General Formula (VA) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (V) or a pharmaceutically acceptable salt thereof;

[0189] The compound represented by General Formula (V-1A) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (V-1) or a pharmaceutically acceptable salt thereof;

[0190] The compound represented by General Formula (V-2A) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (V-2) or a pharmaceutically acceptable salt thereof;

[0191] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0192] R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in General Formula (V), (V-1) or (V-2).

[0193] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula (I)-(V) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0194] The present disclosure further relates to the use of a compound of Formula (I)-(V) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting and / or degrading TYK2.

[0195] The present disclosure further relates to the use of a compound of Formula (I)-(V) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting and / or degrading TYK2.

[0196] The present disclosure further relates to the use of a compound of Formula (I)-(V) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing a disease or condition mediated by or dependent on TYK2.

[0197] The present disclosure further relates to the use of a compound of Formula (I)-(V) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing an autoimmune disease, an inflammatory disease, and a cancer; in some embodiments, in the manufacture of a medicament for treating and / or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn’s disease, plaque psoriasis, psoriatic arthritis, pustular psoriasis, Sjogren’s syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorder, posterior uveitis, panuveitis, dermatomyositis, scarring alopecia, and asthma.

[0198] The present disclosure also relates to a method of treating and / or preventing a disease or condition mediated by or dependent on TYK2 comprising administering to a patient in need thereof a compound of Formula (I)-(V) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0199] The present disclosure also relates to a method of inhibiting and / or degrading TYK2 comprising administering to a patient in need thereof a compound of Formula (I)-(V) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0200] The present disclosure also relates to a method of treating and / or preventing an autoimmune disease, an inflammatory disease, and a cancer comprising administering to a patient in need thereof a compound of Formula (I)-(V) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0201] The present disclosure further relates to a compound of general formula (I) to (V) or Table A as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0202] The present disclosure further relates to a compound of general formula (I) to (V) or Table A as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a TYK2 inhibitor and / or degrader.

[0203] The present disclosure further relates to a compound of general formula (I) to (V) or Table A as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting TYK2 activity and / or degrading TYK2.

[0204] The present disclosure further relates to a compound of general formula (I) to (V) or Table A as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for treating and / or preventing a disease or disorder mediated by or dependent on TYK2.

[0205] The present disclosure further relates to a compound of general formula (I) to (V) or Table A as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting TYK2 activity and / or degrading TYK2.

[0206] The present disclosure further relates to a compound of general formula (I) to (V) or Table A as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or disorder mediated by or dependent on TYK2.

[0207] The present disclosure further relates to a compound of general formula (I) to (V) or Table A as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing an autoimmune disease, an inflammatory disease, and a cancer; in some embodiments for use in treating and / or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, pustular palmoplantar psoriasis, Sjogren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, scarring alopecia, and asthma.

[0208] In some embodiments of the present disclosure, the disease or disorder mediated by or dependent on TYK2 is selected from an autoimmune disease, an inflammatory disease, and a cancer.

[0209] In some embodiments of the disclosure, the disease or disorder mediated or dependent by TYK2 or autoimmune, inflammatory and cancer diseases are selected from Psoriasis, Lupus, Inflammatory Bowel Disease, Multiple Sclerosis, Rheumatoid Arthritis, Crohn's Disease, Plaque Psoriasis, Psoriatic Arthritis, Palmoplantar Pustulosis, Sjogren Syndrome, Ulcerative Colitis, Alopecia Areata, Hidradenitis Suppurativa, Immune Disorder, Posterior Uveitis, Panuveitis, Dermatomyositis, Scarring Alopecia and Asthma; in some embodiments they are selected from Psoriasis (Ps), Lupus, Inflammatory Bowel Disease (IBD), Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Crohn's Disease, Plaque Psoriasis, Palmoplantar Pustulosis, Sjogren Syndrome (SS), Ulcerative Colitis (UC), Alopecia Areata (AA), Hidradenitis Suppurativa (HS), Immune Disorder, Posterior Uveitis, Panuveitis, Dermatomyositis (DM), Scarring Alopecia and Asthma. Syndrome), Systemic Lupus Erythematosus, Psoriatic Arthritis, Ulcerative Colitis, Lichen Planopilaris, Alopecia Areata, Hidradenitis Suppurativa, Generalized Pustular Psoriasis, Erythrodermic Psoriasis, Immune Disorders, Uveitis Posterior, Uveitis Totalis, Dermatomyositis, Inflammatory Epidermal Genodermatoses, Active Discoid and / or Subacute Cutaneous Lupus Erythematosus (DLE / SCLE), Lupus Nephritis, Scarring Alopecia, Non- Segmental Vitiligo, Adult Active Systemic Lupus Erythematosus, atopic dermatitis, Uveitis Posterior Non-Infectious Uveitis, Intermediate Noninfectious Panuveitis, Asthma, Respiratory Distress Syndrome, Bacterial Pneumonia, Systemic Inflammatory Response Syndrome, T-cell Acute Lymphoblastic Leukemia, COVID-19, and Neuroinflammation Disorders.

[0210] The active compounds can be prepared into such forms as are suitable for administration by any appropriate route, and the active compound is preferably in unit dosage form, or in a form that the patient can self-administer in a single dose. The expression unit dose of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, vials of aqueous or dilute alcoholic solutions, powders, granules, lozenges, suppositories, reconstitutable powders or liquid preparations.

[0211] As a general guide, a suitable unit dose can be 0.1 to 1000 mg.

[0212] The pharmaceutical composition of the present disclosure can contain one or more auxiliary substances selected from diluents, binders, humectants, disintegrants, or excipients, etc. in addition to the active compound, depending on the method of administration. The composition can contain 0.1 to 99% by weight of the active compound, depending on the method of administration.

[0213] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0214] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 1-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 2-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof.

[0215] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2-98% of a pharmaceutically acceptable excipient.

[0216] The pharmaceutical composition containing the active ingredient can be in a form suitable for oral use, for example, as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. The oral compositions can be prepared according to any method known in the art of pharmaceutical preparation, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable drug preparation. Tablets contain the active ingredient in admixture with a nontoxic pharmaceutically acceptable excipient that is suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. Examples of coating agents include polymeric substances such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and ethylcellulose, and waxes.

[0217] Oral preparations can also be provided in the form of soft gelatin capsules wherein the active ingredient is dissolved or suspended in an inert, solid diluent or wherein the active ingredient is dissolved or mixed with a water-soluble carrier or an oil vehicle.

[0218] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension can also include one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0219] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil or mineral oil with or without the addition of a fractionated medicinal carrier. The oil suspensions can contain a thickening agent. Sweetening agents and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant.

[0220] The pharmaceutical compositions of this disclosure can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil designed for injection. Suitable emulsifying agents can be naturally-occurring phosphatides, such as soybean phophatide, and the like. Additional suitable excipients or vehicles that can be employed with the compositions of this disclosure include, but are not limited to, sterile, fixed oils, which can be used to dissolve the active ingredient, and which can be used as a solvent or suspending medium. Suitable fixed oils are, for example, synthetic mono- or diglycerides, and can include fatty acids, such as oleic acid.

[0221] The pharmaceutical compositions of this disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. The active ingredient can be dissolved or suspended in the appropriate solvent or vehicle, such as water, Ringer's solution, or isotonic sodium chloride solution. Sterile injectable preparations can also be prepared using a sterile fixed oil, which can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids can also be used as a solvent or suspending medium. The active ingredient can be dissolved or suspended at the appropriate concentration in the appropriate solvent or vehicle.

[0222] The pharmaceutical compositions of this disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. The active ingredient can be dissolved or suspended in the appropriate solvent or vehicle, such as water, Ringer's solution, or isotonic sodium chloride solution. Sterile injectable preparations can also be prepared using a sterile fixed oil, which can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids can also be used as a solvent or suspending medium. The active ingredient can be dissolved or suspended at the appropriate concentration in the appropriate solvent or vehicle.

[0223] The compounds of this disclosure can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0224] The dosage of the drug depends on various factors as is well known to those skilled in the art, including but not limited to the following: the activity of the particular compound used, the age of the patient, the body weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc. In addition, the optimal therapeutic regime, such as the mode of treatment, the daily amount of the compound, or the kind of the pharmaceutically acceptable salt, can be verified according to the conventional therapeutic regime.

[0225] Terminology

[0226] Unless otherwise indicated, the terms used in the specification and claims are to be taken in their ordinary meaning.

[0227] The term "alkyl" refers to saturated straight chain or branched chain aliphatic hydrocarbon groups having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkyl group preferably has from 1 to 12 carbon atoms (i.e., C 1-10 The alkyl group preferably has from 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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, 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 various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0228] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1- 10 The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-8 The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-6alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. The alkylene group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halo, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0229] The term "alkenyl" refers to an alkyl group that contains at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6 The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-12 The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0230] The term "alkenylene" refers to a divalent alkenyl group, wherein alkenyl is as defined above.

[0231] The term "alkynyl" refers to an alkyl group that contains at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above, having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6 The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-12 The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0232] The term "alkenylene" refers to a divalent alkenyl group, wherein alkenyl is as defined above.

[0233] The term "alkoxy" refers to -0-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propyloxy, and butyloxy, and the like. The alkoxy group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0234] The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methylthio, ethylthio, propylthio, and butylthio, and the like. The alkylthio group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0235] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or a multicyclic system (i.e., multicyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3- to 12-membered cycloalkyl) or 3 to 10 ring atoms (i.e., 3- to 10-membered cycloalkyl), more preferably 3 to 8 ring atoms (i.e., 3- to 8-membered cycloalkyl), most preferably 3 to 6 ring atoms (i.e., 3- to 6-membered cycloalkyl), 4 to 7 ring atoms (i.e., 4- to 7-membered cycloalkyl), or 5 or 6 ring atoms (i.e., 5- or 6-membered cycloalkyl); most preferably 5 or 6 ring atoms.

[0236] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0237] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0238] The term "spirocycloalkyl" refers to a polycyclic ring system sharing one carbon atom between rings (referred to as a spiro atom), which can contain one or more double bonds within the rings, or which can contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur within the rings (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-), provided that at least one fully carbon ring is present and the point of attachment is on the fully carbon ring, having from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered spirocycloalkyl). The spirocycloalkyl group preferably has from 6 to 14 ring atoms (i.e., 6- to 14-membered spirocycloalkyl), more preferably from 7 to 10 ring atoms (i.e., 7- to 10-membered spirocycloalkyl). The spirocycloalkyl group includes mono- and polyspirocycloalkyl groups (e.g., dispirocycloalkyl groups, etc.), preferably a monospriocycloalkyl group or a dispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospriocycloalkyl group. Non-limiting examples include:

[0239] which can be attached at any position;

[0240] etc.

[0241] The term "fused cycloalkyl" refers to a polycyclic ring system sharing two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused with one or more monocyclic cycloalkyl, or a monocyclic cycloalkyl fused with one or more of heterocyclyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic cycloalkyl, which can contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered fused cycloalkyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3- membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples include:

[0242] which can be attached at any position; and the like.

[0243] The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system sharing two non-adjacent carbon atoms between the rings, which can contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5- to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has 6 to 14 carbon atoms (i.e., 6- to 14-membered bridged cycloalkyl), more preferably 7 to 10 carbon atoms (i.e., 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0244] which can be attached at any position.

[0245] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0246] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from the group consisting of nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-) in the ring(s) and having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered heterocyclyl). The heterocyclyl group preferably has from 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl) or from 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclyl) or from 7 to 12 ring atoms (i.e., 7- to 12-membered heterocyclyl); further preferably from 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl); more preferably from 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl), from 4 to 7 ring atoms (i.e., 4- to 7-membered heterocyclyl), or 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl); most preferably 5 or 6 ring atoms.

[0247] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, and the like.

[0248] Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups.

[0249] "Nitrogen-containing heterocyclyl" refers to a heterocyclyl group having at least one (e.g., 1, 2, 3, or 4) nitrogen atom in the heterocyclyl ring, which is defined above. Preferred are 3- to 10-membered nitrogen-containing heterocyclyl groups, more preferred are 4- to 7-membered nitrogen-containing heterocyclyl groups, and most preferred are 5- or 6-membered nitrogen-containing heterocyclyl groups.

[0250] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system which shares one atom (referred to as a spiro atom) between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-), provided that at least one monocyclic heterocyclyl is contained and the point of attachment is on the monocyclic heterocyclyl, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered spiroheterocyclyl). The spiroheterocyclyl preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocyclyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered spiroheterocyclyl). The spiroheterocyclyl includes mono- and polyspiroheterocyclyl (e.g., dispiroheterocyclyl, etc.), preferably a monosprioheterocyclyl or dispiroheterocyclyl, more preferably a 3- membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monosprioheterocyclyl. Non-limiting examples include:

[0251] etc.

[0252] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system sharing adjacent ring atoms between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., N-oxide; said sulfur optionally oxidized, i.e., sulfoxide or sulfone, but not including -O-O-, -O-S-, or -S-S-) within the ring, which is fused to a monocyclic heterocyclyl group or to one or more monocyclic heterocyclyl groups, or to one or more of a cycloalkyl, aryl, or heteroaryl group, with the point of attachment being on the monocyclic heterocyclyl group, and having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused heterocyclyl). The fused heterocyclyl group preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocyclyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered fused heterocyclyl). The fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (e.g., tricyclic fused heterocyclyl groups, tetracyclic fused heterocyclyl groups, etc.), preferably bicyclic fused heterocyclyl groups or tricyclic fused heterocyclyl groups, more preferably 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused heterocyclyl groups. Non-limiting examples include:

[0253] etc.

[0254] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system sharing two non-adjacent ring atoms between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., N-oxide; said sulfur optionally oxidized, i.e., sulfoxide or sulfone, but not including -O-O-, -O-S-, or -S-S-) within the ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered bridged heterocyclyl). The bridged heterocyclyl group preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocyclyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocyclyl). The bridged heterocyclyl group includes bicyclic and polycyclic bridged heterocyclyl groups (e.g., tricyclic bridged heterocyclyl groups, tetracyclic bridged heterocyclyl groups, etc.), preferably bicyclic bridged heterocyclyl groups or tricyclic bridged heterocyclyl groups. Non-limiting examples include:

[0255] etc.

[0256] Heterocyclyl can be substituted or non-substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0257] The term "aryl" refers to a monocyclic all-carbon aromatic ring having a conjugated pi-electron system (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 6- to 20-membered aryl). The aryl group preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered aryl), more preferably 6 to 10 ring atoms (i.e., 6- to 10-membered aryl). The monocyclic aryl group is exemplified by phenyl. The polycyclic aryl group is exemplified by, without limitation, naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes phenyl or naphthyl fused with one or more heterocyclyl or cycloalkyl groups, where the point of attachment is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, which is exemplified by, without limitation:

[0258]

[0259] and the like.

[0260] Aryl can be substituted or non-substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0261] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl group), more preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and most preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group).

[0262] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0263] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0264]

[0265] wait.

[0266] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0267] The term "cycloalkyloxy" means -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0268] The term "heterocyclyloxy" means -O-heterocyclyl, wherein heterocyclyl is as defined above.

[0269] The term "aryloxy" means -O-aryl, wherein aryl is as defined above.

[0270] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0271] The term "cycloalkylalkyl" means alkyl substituted by one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0272] The term "heterocyclylalkyl" means alkyl substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0273] The term "arylalkyl" means alkyl substituted by one or more aryl groups, wherein aryl and alkyl are as defined above.

[0274] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0275] The term "haloalkyl" means alkyl substituted by one or more halogen, wherein alkyl is as defined above.

[0276] The term "haloalkoxy" means alkoxy substituted by one or more halogen, wherein alkoxy is as defined above.

[0277] The term "hydroxyalkyl" means alkyl substituted by one or more hydroxy groups, wherein alkyl is as defined above.

[0278] The term "hydroxyalkoxy" means alkoxy substituted by one or more hydroxy groups, wherein alkoxy is as defined above.

[0279] The term "alkoxyalkyl" means alkyl substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; preferably -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, methoxyethyl.

[0280] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0281] The term "hydroxy" means -OH.

[0282] The term "amino" means -NH2.

[0283] The term "cyano" means -CN.

[0284] The term "nitro" means -NO2.

[0285] The term "oxo" or "oxo group" means "=O".

[0286] The term "carbonyl" means C=0.

[0287] TBS means tert-butyldimethylsilyl group.

[0288] The term "amido" means -CONH2.

[0289] The term "acetyl" means C(O)CH3.

[0290] The term "amino protecting group" means an easily removed group which is introduced to an amino group in order to prevent the amino group from reacting at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), formyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), and the like.

[0291] The compounds of the present disclosure can exist in particular stereoisomeric forms. The term "stereoisomers" refers to isomers having the same structure except they have atoms in space arranged differently. This includes cis- and trans- (or E- and Z-) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomeric forms, diastereomers, (D)- and (L)- isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds of the present disclosure can present additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are encompassed within the scope of the present disclosure. The optically active (-)- and (+)- isomers, (R)- and (S)- enantiomeric forms, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis, or by chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is present in the molecule, by forming a diastereomeric salt with an appropriate optically active acid or base, and then resolving the diastereomeric salt by conventional means well-known in the art. In addition, the separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0292] In the chemical structures of the compounds of the present disclosure, the bond indicates unspecified configuration, i.e., if chiral isomers are present in the chemical structure, the bond may be or both two configurations. For all carbon-carbon double bonds, both the Z and E configurations are included even if only one configuration is named.

[0293] The compounds of the present disclosure can contain all modes of rotation isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" refers to stereoisomers that result from restricted rotation about a single bond, in which the energy difference due to steric strain or other contributing factors is high enough to allow separation of individual conformational isomers. For example, certain compounds of the present disclosure can exist as a mixture of atropisomers (e.g., an equimolar mixture, a mixture enriched in one atropisomer, etc.) or as a purified atropisomer.

[0294] The compounds of the present disclosure can exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric forms" refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to another isomeric form. It includes all possible tautomers, in either the single isomeric form or in mixtures of any proportion of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. An example of a lactam-lactim equilibrium is shown below:

[0295] As when referring to pyrazolyl, it is understood to include either one of the following two structures or a mixture of both tautomers:

[0296] All tautomeric forms are within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[0297] The compounds of the present disclosure include all suitable isotopic variations of the compounds. The term "isotopic variations" means the compounds having the same atomic numbering but having at least one atom replaced by an atom having the same atomic number but an atomic mass different from the dominant natural isotopic mass. Examples of isotopes that can be present in the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S,34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, preferably deuterium.

[0298] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic composition variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, wherein the replacement of deuterium can be partial or complete, and the partial replacement of deuterium means that at least one hydrogen is replaced with at least one deuterium.

[0299] When a position is specifically designated as deuterium D, the position should be understood as having deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The example compound having deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium can be at least 15% deuterium incorporation, at least 30% deuterium incorporation, at least 45% deuterium incorporation, at least 50.1% deuterium incorporation, at least 52.5% deuterium incorporation, at least 60% deuterium incorporation, at least 67.5% deuterium incorporation, at least 75% deuterium incorporation, at least 82.5% deuterium incorporation, at least 90% deuterium incorporation, at least 95% deuterium incorporation, at least 97% deuterium incorporation, at least 99% deuterium incorporation, at least 99.5% deuterium incorporation, or higher abundance of deuterium.

[0300] “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and thus includes both instances in which the event or circumstance occurs and instances in which it does not. For example, “C 1- 6alkyl” includes instances in which the alkyl group is substituted with halo or cyano and instances in which the alkyl group is not substituted with halo or cyano.

[0301] "Substituted" or "substitution" means that one or more hydrogen atoms, preferably 1, 2, or 3, more preferably 1 to 3, of a group are independently of each other replaced by a corresponding number of substituents. It is possible or not possible to substitute, as determined by one skilled in the art (by experiment or theory) without undue effort. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated bond, such as an alkene.

[0302] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or pharmaceutically acceptable salts thereof with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism, to facilitate absorption, and thereby facilitate biological utilization.

[0303] "Pharmaceutically acceptable salt" means a salt of a compound of the disclosure that is safe and effective for use in a mammal, and possesses the desired biological activity. The salts can be prepared from the final isolated and purified compound, or by reacting a suitable group with a suitable base or acid. Alkali bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium and potassium hydroxides, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids, as well as organic acids.

[0304] The term "pharmaceutically acceptable" as used herein means that these compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0305] As used herein, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise.

[0306] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be appreciated by those skilled in the art, numbers are often given only to the nearest whole number for the sake of readability and ease of comprehension, not to limit the parameter.

[0307] Synthetic methods of the compounds of the disclosure

[0308] To achieve the purposes of the present disclosure, the present disclosure adopts the following technical solutions:

[0309] Scheme One

[0310] The present disclosure provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0311] The compound represented by general formula (IA) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

[0312] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0313] Z 1 , G 1 , G 2 , G 3 , L 1 to L 6 , E, R 3 , R 5 and R 6 are as defined in general formula (I).

[0314] Scheme II

[0315] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0316] The compound represented by general formula (IIA) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0317] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0318] Z 1 , E, L 1 to L 6 , R 3 , R 5 and R 6 are as defined in general formula (II).

[0319] Scheme III

[0320] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0321] The compound represented by general formula (IIIA) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

[0322] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0323] Z1 , E, L 1 to L 6 , R 3 , R 5 and R 6 as defined in general formula (III).

[0324] Scheme four

[0325] The present disclosure provides a method for preparing a compound represented by general formula (IV-1), (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0326] The compound represented by general formula (IVA) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof;

[0327] The compound represented by general formula (IV-1A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof;

[0328] The compound represented by general formula (IV-2A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof;

[0329] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0330] Z 1 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in general formula (IV), (IV-1) or (IV-2).

[0331] Scheme five

[0332] The present disclosure provides a method for preparing a compound represented by general formula (V), (V-1) and (V-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0333] The compound represented by general formula (VA) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof;

[0334] The compound represented by General Formula (V-1A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by General Formula (V-1) or a pharmaceutically acceptable salt thereof;

[0335] The compound represented by General Formula (V-2A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by General Formula (V-2) or a pharmaceutically acceptable salt thereof;

[0336] wherein, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom;

[0337] R 1a , R 1 , R 2 , R 3 , R 5 , R 6 , L 1 to L 6 , R 7 , R q and s are as defined in General Formula (V), (V-1) or (V-2).

[0338] The reagent that provides acidic conditions in the above synthesis scheme includes, but is not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf; preferably trifluoroacetic acid.

[0339] The reaction of the above step is preferably carried out in a solvent, and the solvent used includes, but is not limited to, pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and a mixture thereof. DETAILED DESCRIPTION

[0340] The present disclosure is further described in conjunction with the following examples, which are not intended to limit the scope of the present disclosure.

[0341] Examples

[0342] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is expressed in 10 -6The NMR measurement is carried out by using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0343] The MS measurement is carried out by using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatograph-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0344] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0345] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0346] The high performance liquid chromatography (HPLC) analysis uses an Agilent HPLC 1200 DAD, an Agilent HPLC 1200 VWD, and a Waters HPLC e2695-2489 high pressure liquid chromatograph.

[0347] The chiral HPLC analysis measurement uses an Agilent 1260 DAD high performance liquid chromatograph.

[0348] The high performance liquid preparation uses a Waters 2545-2767, a Waters 2767-SQ Detector 2, a Shimadzu LC-20AP, and a Gilson GX-281 preparative chromatograph.

[0349] The chiral preparation uses a Shimadzu LC-20AP preparative chromatograph.

[0350] The CombiFlash rapid preparation instrument uses a Combiflash Rf200 (TELEDYNE ISCO).

[0351] The thin layer chromatography silica gel plate uses a Yantai Huanghai HSGF254 or a Qingdao GF254 silica gel plate. The silica gel plate used in the thin layer chromatography (TLC) has a specification of 0.15 mm to 0.2 mm, and the thin layer chromatography separation and purification product has a specification of 0.4 mm to 0.5 mm.

[0352] The silica gel column chromatography generally uses 200-300 mesh silica gel of Yantai Huanghai as the carrier.

[0353] The determination of the average inhibition rate of the kinase and IC 50 The determination of the average inhibition rate of the kinase and IC

[0354] The known starting materials of the present disclosure can be synthesized according to the methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Daejung Chemicals, etc.

[0355] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0356] The argon atmosphere or the nitrogen atmosphere refers to that a reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0357] The hydrogen atmosphere refers to that a reaction bottle is connected to a hydrogen balloon with a volume of about 1 L.

[0358] The pressurized hydrogenation reaction uses a Parr 3916EKX type hydrogenation instrument and a Qinglan QL-500 type hydrogen generator or an HC2-SS type hydrogenation instrument.

[0359] The hydrogenation reaction is generally vacuumed, filled with hydrogen, and the operation is repeated 3 times.

[0360] The microwave reaction uses a CEM Discover-S 908860 type microwave reactor.

[0361] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0362] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-30°C.

[0363] The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent system of the column chromatography used for purifying the compound, and the developing agent system of the thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of triethylamine and an alkaline or acidic reagent such as acetic acid can also be added for adjustment.

[0364] Example 1

[0365] 5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H- [1,2'-bipyridinyl]-3-yl)amino)-7-(methylamino)-N-(pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 1

[0366] First step

[0367] 5-chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3- carboxylic acid 1b

[0368] Ethyl 5-chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate 1a (5 g, 13.3 mmol, prepared by the method disclosed in the specification page 14 Preparation 3 of patent application “WO2020055636A1”) was dissolved in water (40 mL) and tetrahydrofuran (80 mL), lithium hydroxide monohydrate (2.23 g, 53.1 mmol) was added, and the reaction was stirred at 30 °C for 48 h. The reaction solution was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate (50 mL x 1), the aqueous phase was adjusted to pH 5 with 1M hydrochloric acid, extracted with dichloromethane (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1b (2.9 g). The product was used directly in the next step without purification.

[0369] MS m / z (ESI): 345 [M-1].

[0370] Second step

[0371] 5-chloro-7-((4-methoxybenzyl)(methyl)amino)-N-(pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 1c

[0372] To a solution of compound 1b (450 mg, 1.3 mmol) and 3-amino-2-oxo-2H-[1,2’-bipyridinyl]-5’-carboxylic acid methyl ester 1d (140 mg, 570.8 μmol, prepared by the method disclosed in Example 1.8 on page 507 of the specification of patent application “WO2023076161”) in 1,4-dioxane (5 mL) was added palladium acetate (25.6 mg, 114.1 μmol), 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene (71.1 mg, 106.7 μmol), cesium carbonate (558 mg, 1.7 mmol) and the reaction was stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using eluent system A to give the title compound 1e (200 mg, yield: 56.1%).

[0373] MS m / z (ESI): 415.2 [M+1].

[0374] Third step

[0375] 3-((7-((4-methoxybenzyl)(methyl)amino)-3-(pyrrolidin-1-ylaminocarbonyl)pyrazolo[1,5- a]pyrimidin-5-yl)amino)-2-oxo-2H-[1,2’-bipyridinyl]-5’-carboxylic acid methyl ester 1e

[0376] To a solution of compound 1c (213 mg, 513 μmol) and 3-amino-2-oxo-2H-[1,2’-bipyridinyl]-5’-carboxylic acid methyl ester 1d (140 mg, 570.8 μmol, prepared by the method disclosed in Example 1.8 on page 507 of the specification of patent application “WO2023076161”) in 1,4-dioxane (5 mL) was added palladium acetate (25.6 mg, 114.1 μmol), 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene (71.1 mg, 106.7 μmol), cesium carbonate (558 mg, 1.7 mmol) and the reaction was stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using eluent system A to give the title compound 1e (200 mg, yield: 56.1%).

[0377] MS m / z (ESI): 624.2 [M+1].

[0378] Fourth step

[0379] 3-((7-((4-methoxybenzyl)(methyl)amino)-3-(pyrrolidin-1-ylaminocarbonyl)pyrazolo[1,5- a]pyrimidin-5-yl)amino)-2-oxo-2H-[1,2’-bipyridinyl]-5’-carboxylic acid 1f

[0380] Compound 1e (240 mg, 384.8 μmol) was dissolved in water (2 mL) and tetrahydrofuran (10 mL), lithium hydroxide monohydrate (80.7 mg, 1.9 mmol) was added, the reaction was stirred for 16 hours, the reaction solution was concentrated under reduced pressure, diluted with water, the pH was adjusted to 5 with 1M hydrochloric acid, a solid was precipitated, filtered, and the filter cake was dried to obtain the crude title compound 1f (200 mg). The product was used directly in the next step without purification.

[0381] MS m / z (ESI): 608.1 [M-1].

[0382] Fifth step

[0383] 5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H- [1,2'-bipyridinyl]-3-yl)amino)-7-((4-methoxybenzyl)(methyl)amino)-N- (pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 1h

[0384] The crude compound 1f (52 mg, 82.3 μmol) and 3-(3-methyl-2-oxo-4-(2,7- diazaspiro[3.5]non-7-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione-2,2,2 trifluoroacetate salt 1g (55.1 mg, 110.8 μmol, prepared by the method disclosed in the specification of patent application “WO2023076161” on page 546 Example 1.31) were dissolved in N,N-dimethylacetamide (2 mL), N,N- diisopropylethylamine (55.1 mg, 426.5 μmol) was added, O-(7-azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) (48.6 mg, 127.9 μmol) was added, the reaction was stirred for 2 hours, water was added to the reaction solution, extracted with dichloromethane (10 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1h (a pair of enantiomer mixture, 83 mg). The product was used directly in the next step without purification. MS m / z (ESI): 975.5 [M+1].

[0385] Sixth step

[0386] 5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H- [1,2'-bipyridinyl]-3-yl)amino)-7-(methylamino)-N-(pyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 1

[0387] The crude compound 1h (83 mg, 85.1 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at 110 °C for 1 h. The reaction was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 1 (a mixture of one pair of enantiomers, 10 mg, yield: 13.7%).

[0388] MS m / z (ESI): 855.6 [M+1].

[0389] 1 H NMR (500 MHz, CDCl3): δ 8.92 (s, 1H), 8.47 (dd, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.25-8.20 (m, 1H), 8.14 (dd, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.69 (dd, 1H), 7.03 (d, 1H), 6.87 (d, 1H), 6.62 (s, 1H), 6.43 (t, 1H), 6.30 (d, 1H), 5.49 (s, 1H), 5.26-5.21 (m, 1H), 4.23 (s, 1H), 4.16 (s, 1H), 4.12 (s, 1H), 4.05 (s, 1H), 3.79 (s, 3H), 3.18 (d, 2H), 3.12 (d, 3H), 3.07 (d, 2H), 2.97 (d, 1H), 2.89-2.83 (m, 1H), 2.81-2.72 (m, 2H), 2.28-2.21 (m, 2H), 2.07 (d, 4H), 2.00 (p, 4H).

[0390] Example 2

[0391] N-(3-(difluoromethyl)pyrrolidin-1-yl)-5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridinyl]-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 2

[0392] First Step

[0393] tert-Butyl 3-(difluoromethyl)pyrrolidine-1-carboxylate 2b

[0394] tert-Butyl 3-oxopyrrolidine-1-carboxylate 2a (3.94 g, 21.3 mmol, Shanghai Bide) was dissolved in N,N-dimethylformamide (5 mL), and 2,2-difluoro-2-(triphenylphosphoranyl)ethyl acetate (18.94 g, 53.2 mmol, Shanghai Leyan) was added. The reaction was stirred at 80 °C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2b (500 mg, yield: 10.7%).

[0395] MS m / z (ESI): 163.9 [M-55].

[0396] Second Step

[0397] 3-(difluoromethyl)pyrrolidine hydrochloride 2c

[0398] Compound 2b (500 mg, 2.28 mmol) was dissolved in a 4 M hydrogen chloride solution in 1,4-dioxane (20 mL), and the reaction was stirred for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2c (350 mg). The product was used directly in the next step without purification.

[0399] Third Step

[0400] 3-(difluoromethyl)-1-nitrosopyrrolidine 2d

[0401] The crude compound 2c (350 mg, 2.9 mmol) was dissolved in tetrahydrofuran (5 mL), and tert-butyl nitrite (787.8 mg, 7.6 mmol) was added. The reaction was stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d (430 mg, yield: 98%).

[0402] MS m / z (ESI): 149.1 [M+1].

[0403] Fourth Step

[0404] 3-(difluoromethyl)pyrrolidin-l-amine 2e

[0405] The crude compound 2d (255 mg, 1.72 mmol) was dissolved in methanol (1 mL) and acetic acid (0.3 mL), zinc powder (1.1 g, 17 mmol) was added under ice-bath, the reaction was stirred at room temperature for 16 hours, the reaction solution was diluted with methanol, filtered, the filtrate was concentrated under reduced pressure to give the crude title compound 2e (200 mg), which was used in the next step without purification.

[0406] MS m / z (ESI): 135.0 [M+1].

[0407] Fifth step

[0408] N-(3-(difluoromethyl)pyrrolidin-l-yl)-5-((5'-(7-(l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2- carbonyl)-2-oxo-2H-[l,2'-bipyridinyl]-3-yl)amino)-7-(methylamino)pyrazolo[l,5- a]pyrimidine-3-carboxamide 2

[0409] Using the synthetic route of Example 1, the second step raw material 1- aminopyrrolidine hydrochloride was replaced by compound 2e to obtain the title compound 2 (8 mg, yield: 25.1%) (a pair of enantiomer mixture).

[0410] MS m / z (ESI): 903.2 [M+1].

[0411] 1 ​H NMR (500 MHz, DMSO-d6): δ 11.09 (br, 1H), 9.07 (s, 1H), 8.91 (s, 1H), 8.69 (s, 1H), 8.41 (d, 1H), 8.31-8.29 (m, 1H), 8.24 (s, 1H), 8.00 (d, 1H), 7.97-7.94 (m, 1H), 7.66 (d, 1H), 6.97-6.94 (m, 2H), 6.89-6.85 (m, 2H), 6.43 (t, 1H), 6.23 (s, 1H), 5.37-5.32 (m, 2H), 4.29-4.27 (m, 1H), 4.19-4.16 (m, 1H), 3.89-3.86 (m, 4H), 3.64 (s, 4H), 3.13-3.10 (m, 2H), 3.05-3.03 (m, 1H), 2.95-2.92 (m, 3H), 2.03-1.91 (m, 4H), 1.48-1.45 (m, 1H), 1.24-1.18 (m, 4H), 0.08-0.07 (m, 1H).

[0412] Example 3

[0413] 5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-1H- [1,2'-bipyridinyl]-3-yl)amino)-N',N'-diethyl-7-(methylamino)pyrazolo[1,5- a]pyrimidine-3-carbohydrazide 3

[0414] Using the synthetic route of Example 1, the second step starting material 1- aminopyrrolidine hydrochloride was replaced by 1,1-diethylhydrazine 2,2,2- trifluoroacetate (prepared using the method disclosed in S9a of the literature “Chemical Communications, 2021, vol. 57, #91, p. 12187-12190”) to give the title compound 3 (30 mg, yield: 68.2%) (a mixture of one pair of enantiomers).

[0415] MS m / z (ESI): 857.4 [M+1].

[0416] 1H NMR (500 MHz, CDC13): δ 8.92 (s, 1H), 8.48 (s, 1H), 8.41 (dt, 1H), 8.23 (d, 1H), 8.16-8.11 (m, 1H), 8.08 (d, 2H), 7.68 (dd, 1H), 7.03 (s, 1H), 6.96-6.94 (m, 1H), 6.62 (s, 1H), 6.46 (t, 1H), 6.31 (d, 1H), 5.50 (d, 1H), 5.39-5.35 (m, 1H), 5.22 (dd, 1H), 4.23 (s, 1H), 4.16 (s, 1H), 4.12 (s, 1H), 4.05 (s, 1H), 3.79 (s, 3H), 3.18 (d, 2H), 3.12 (d, 3H), 2.93 (q, 4H), 2.83-2.73 (m, 3H), 2.27-2.22 (m, 2H), 2.03 (s, 4H), 1.67 (d, 1H), 1.24 (t, 6H).

[0417] Example 4

[0418] N-(3,3-difluoroazetidin-l-yl)-5-((5'-(7-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[l,2'-bipyridinyl]-3- yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidine-3-carboxamide 4

[0419] First step

[0420] 3,3-difluoro-l-nitrosoazetidine 4b

[0421] Compound 3,3-difluoroazetidine hydrochloride 4a (30 g, 231.6 mmol) was dissolved in tetrahydrofuran (600 mL), tert-butyl nitrite (67.5 g, 654.6 mmol) was added at 0 °C, the reaction was stirred for 4 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 4b (28.1 g), which was used directly in the next step without purification. MS m / z (ESI): 122.9 [M+l].

[0422] Second step

[0423] 3,3-difluoroazetidine-l -amine hydrochloride 4c

[0424] The crude compound 4b (37 g, 303.1 mmol) was dissolved in methanol (600 mL) and acetic acid (75 mL), and zinc powder (1.4 g, 21.4 mmol) was added portionwise under ice bath. The reaction was stirred at room temperature for 0.5 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (500 mL) and filtered. The filtrate was concentrated under reduced pressure, 1.25 M aqueous sodium hydroxide solution (1.5 L) and 650 mL of 1,4-dioxane were added, and the solution was stirred and cooled to 0 °C. Di-tert-butyl dicarbonate (21 mL) was added, and the reaction was stirred for 30 min. Dichloromethane (500 mL) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (300 mL x 2), and the pH was adjusted to 1 with 1 M hydrochloric acid. The resulting aqueous solution was concentrated under reduced pressure. The residue was dissolved in methanol (450 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was slurried with about 500 mL of tetrahydrofuran and dichloromethane (1:1, V:V), filtered, and dried to obtain the crude title compound 4c (16 g). The product was used directly in the next reaction without purification.

[0425] MS m / z (ESI): 109.0 [M+1].

[0426] Step 3

[0427] N-(3,3-difluoroazetidin-1-yl)-5-((5'-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-oxo-2H-[1,2'-bipyridinyl]-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 4

[0428] Using the synthetic route of Example 1, the second step raw material 1-aminopyrrolidine hydrochloride was replaced with compound 4c to obtain the title compound 4 (a mixture of one pair of enantiomers, 4 mg, yield: 6.5%).

[0429] MS m / z (ESI): 877.4 [M+1].

[0430] 1H NMR (500 MHz, CDC13): δ 8.90 (s, 2H), 8.37 (s, 1H), 8.32 (d, 1H), 8.21 (d, 1H), 8.13-8.10 (m, 3H), 7.69 (d, 1H), 7.05-6.84 (m, 2H), 6.60-6.54 (m, 2H), 6.30 (d, 1H), 5.50 (s, 1H), 5.36-5.33 (m, 1H), 5.20 (dd, 1H), 4.44 (t, 4H), 4.21-4.02 (m, 4H), 3.76 (s, 3H), 3.16-3.14 (m, 2H), 3.10 (d, 3H), 2.96-2.93 (m, 1H), 2.86-2.72 (m, 3H), 2.22 (t, 2H), 2.03-2.00 (m, 3H).

[0431] Example 5

[0432] 5-((2-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-6-oxo-1,3,4,6- tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 5

[0433] First step

[0434] (1S,2S)-2-(Dibenzylamino)cyclobutan-1-ol 5b-1

[0435] (1R,2R)-2-(Dibenzylamino)cyclobutan-1-ol 5b-2

[0436] The compound rac-(1R,2R)-2-(dibenzylamino)cyclobutan-1-ol 5a (440 g, 1645 mmol, prepared by the method disclosed in the specification of patent application “WO20200231594A1” on page 108 Example-18) was separated by chiral column (Waters SFC 150, column: 40*250 mm, 10 pm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol (containing 0.1% 7.0 mol / L ammonium methanol solution), gradient ratio: A:B = 85:15, flow rate: 145 mL / min) to obtain the title compound 5b-1 (238.2 g, yield: 54.1%) and 5b-2 (239.3 g, yield: 54.3%).

[0437] Single configuration compound (shorter retention time): 5b-1 (238.2 g).

[0438] MS m / z(ESI):268.2[M+1].

[0439] Chiral HPLC analysis: retention time 1.698 minutes, purity: 99% (chromatographic column: 100*3mm, 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5mL / min).

[0440] Single configuration compound (longer retention time): 5b-2 (239.3 g).

[0441] MS m / z(ESI):268.2[M+1].

[0442] Chiral HPLC analysis: retention time 2.452 minutes, purity: 99% (chromatographic column: 100*3mm, 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 85:15, flow rate: 1.5mL / min).

[0443] Step 2

[0444] (1R,2R)-N,N-Dibenzyl-2-methoxycyclobutane-1-amine 5c

[0445] Compound 5b-2 (205 g, 766.7 mmol) was dissolved in tetrahydrofuran (2500 mL), and potassium tert-butoxide (112.8 g, 1 mol) was added at 0°C. The mixture was stirred and reacted for 30 minutes. Iodomethane (131 g, 922.9 mmol) was added and stirred and reacted for 4 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (500 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 5c (192.4 g, yield: 89.1%).

[0446] MS m / z(ESI):282.2[M+1].

[0447] Step 3

[0448] (1R,2R)-2-Methoxycyclobutane-1-amine hydrochloride 5d

[0449] Compound 5c (192 g, 682.3 mmol) was dissolved in methanol (2000 mL), 10% palladium carbon catalyst (wet) (76.8 g) was added, hydrogen was replaced, the reaction was stirred for 16 hours, the reaction solution was filtered, 4M hydrogen chloride solution in 1,4-dioxane (260 mL) was added to the filtrate in an ice bath, the reaction was stirred for 30 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound 5d (98 g). The product was used directly in the next step without purification.

[0450] Fourth step

[0451] 3-bromo-6-(hydroxymethyl)pyridin-2(lH)-one 5f

[0452] Methyl 5-bromo-6-oxo-l,6-dihydropyridine-2-carboxylate 5e (5 g, 20.32 mmol, Shanghai Bide) was dissolved in tetrahydrofuran (50 mL), 2M lithium borohydride solution in tetrahydrofuran (12 mL) was added under ice bath, the reaction was stirred at room temperature for 16 hours, the reaction solution was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5f (3.6 g, yield: 86.8%).

[0453] MS m / z (ESI): 203.9 [M+1].

[0454] Fifth step

[0455] 3-bromo-6-(chloromethyl)pyridin-2(lH)-one 5g

[0456] Compound 5f (2.5 g, 12.25 mmol) was dissolved in dichloromethane (40 mL), sulfurous chloride (5.83 g, 49 mmol) and a few drops of N,N-dimethylformamide were added under ice bath, the reaction was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 5g (2.7 g, yield: 99%).

[0457] MS m / z (ESI): 221.9 [M+1].

[0458] Sixth step

[0459] 3-bromo-6-(((2-hydroxyethyl)amino)methyl)pyridin-2(lH)-one 5h

[0460] Compound 5g (200 mg, 899.01 μmol) was dissolved in N,N-dimethylacetamide (20 mL), ethanolamine (164.74 mg, 2.7 mmol) was added, the reaction was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound 5h (222 mg). The product was used directly in the next step without purification.

[0461] MS m / z (ESI): 247.1 [M+1].

[0462] Seventh step

[0463] ((5-bromo-6-oxo-l,6-dihydropyridin-2-yl)methyl)(2-hydroxyethyl)carbamic acid tert-butyl ester 5i

[0464] The crude compound 5h (222 mg, 898.46 pmol) was dissolved in dichloromethane (20 mL), triethylamine (272.2 mg, 2.7 mmol), di-tert-butyl dicarbonate (588.2 mg, 2.7 mmol) were added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5i (300 mg, yield: 96.1%).

[0465] MS m / z (ESI): 347.2 [M+1].

[0466] Eighth step

[0467] 7-bromo-6-oxo-l,3,4,6-tetrahydro-2H-pyrido[l,2-a]pyrazine-2-carboxylic acid tert-butyl ester 5j

[0468] The compound 5i (300 mg, 864 pmol) was dissolved in tetrahydrofuran (10 mL), triphenylphosphine (226.6 mg, 864.04 pmol), diisopropyl azodicarboxylate (174.7 mg, 864.04 pmol) were added, the reaction was stirred for 16 hours, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5j (80 mg, yield: 28%).

[0469] MS m / z (ESI): 329.2 [M+1].

[0470] Ninth step

[0471] 5-amino-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid ethyl ester 5k

[0472] The compound la (0.5 g, 1.39 mmol) was dissolved in 7M ammonia methanol solution (10 mL), the reaction was stirred in a sealed tube at 120 °C for 16 hours, after the reaction solution was reduced to room temperature, it was concentrated under reduced pressure, methanol was added to the residue, it was filtered, the filter cake was washed with ethyl acetate, and after drying, the crude title compound 5k (100 mg) was obtained, the product was used directly in the next step reaction without purification.

[0473] MS m / z (ESI): 356.2 [M+1].

[0474] Tenth step

[0475] 7-((3-(Ethoxycarbonyl)-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[l,5- a]pyrimidin-5-yl)amino)-6-oxo-l,3,4,6-tetrahydro-2H-pyrido[l,2-a]pyrazine-2- carboxylic acid tert-butyl ester 5l

[0476] Compound 5k (72.8 mg, 205 μmol) was dissolved in 1,4-dioxane (5 mL), compound 5j (67.5 mg, 205 μmol), tris(dibenzylideneacetone)dipalladium (37.5 mg, 41 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.7 mg, 41 μmol), cesium carbonate (133.6 mg, 410 μmol) were added, and the mixture was replaced with nitrogen and reacted at 100 °C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5l (90 mg, yield: 72.7%).

[0477] MS m / z (ESI): 604.5 [M+1].

[0478] Eleventh step

[0479] 5-((2-(tert-Butoxycarbonyl)-6-oxo-l,3,4,6-tetrahydro-2H-pyrido[l,2-a]pyrazin-7-yl)amino)- 7-((4-methoxybenzyl)(methyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid 5m

[0480] Compound 5l (90 mg, 149 μmol) was dissolved in methanol (2 mL), water (2 mL) and tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (62.6 mg, 1.5 mmol) was added. The mixture was reacted at 60 °C for 4 hours, and after the reaction solution was cooled to room temperature, water was added for dilution, and the pH was adjusted to 3-4 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5m (80 mg). The product was used directly in the next reaction without purification.

[0481] MS m / z (ESI): 576.5 [M+1].

[0482] Twelfth step

[0483] Thirteenth step

[0484] 7-((7-((4-methoxybenzyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)aminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester 5n

[0485] Compound 5m (80 mg, 139 μmol), compound 5d (42 mg, 305 μmol) were dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (53.8 mg, 416.9 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (68.6 mg, 180.6 μmol) were added, the reaction was stirred for 14 hours, water was added to the reaction solution, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5n (35 mg, yield: 38.2%).

[0486] MS m / z (ESI): 659.6 [M+1].

[0487] Thirteenth step

[0488] N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride 5o

[0489] Compound 5n (20 mg, 30.3 μmol) was dissolved in dichloromethane (5 mL), 4M hydrogen chloride solution in 1,4-dioxane (1 mL) was added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 5o (13 mg), which was used directly in the next step without purification.

[0490] MS m / z (ESI): 439.2 [M+1].

[0491] Fourteenth step

[0492] 5-((2-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-6-oxo-1,3,4,6- tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 5

[0493] Compound 5o (13 mg, 27.4 μmol), compound 1g (13.6 mg, 27.4 μmol), N,N- diisopropylethylamine (19.2 mg, 148.3 μmol) were dissolved in dichloromethane (1 mL), a solution of triphosgene (2.8 mg, 9.6 μmol) in dichloromethane (0.5 mL) was added under ice-bath, the reaction was stirred for 14 h, the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to give the title compound 5 (a pair of diastereoisomer mixture, 4 mg, yield: 16%).

[0494] MS m / z (ESI): 848.5 [M+1].

[0495] 1 H NMR (500 MHz, CDCl3): δ 8.42-8.31 (m, 2H), 7.98 (d, 1H), 7.02 (s, 1H), 6.90 (d, 1H), 6.61 (d, 1H), 6.26 (d, 2H), 5.48 (s, 1H), 5.37 (d, 1H), 5.21 (d, 1H), 4.61-4.56 (m, 1H), 4.52 (s, 1H), 4.43 (t, 1H), 3.90-3.70 (m, 6H), 3.39 (s, 3H), 3.11 (d, 3H), 2.74 (s, 5H), 2.24 (t, 2H), 2.03 (s, 4H), 1.28 (d, 8H), 0.91 (d, 2H).

[0496] Example 6

[0497] 5-(((2aS,8aR)-7-(4-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidine-1-carbonyl)-6-fluoro-1,2,2a,8a- tetrahydrobenzo[b]cyclobutene[e][1,4]dioxin-4-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6

[0498] First step

[0499] 2-(benzyloxy)cyclobutan-1-one 6b

[0500] Compound 6b (racemic, 43.8 g, yield: 57.3%) was obtained by mixing 1,2-bis(trimethylsilyloxy)cyclobutene 6a (100 g, 433.9 mmol, Jiangsu Aikang) and benzyl alcohol (46.9 g, 433.9 mmol) in 4 M hydrogen chloride solution in 1,4-dioxane (300 mL) and reacting at 80 °C for 4 hours, concentrating the reaction solution under reduced pressure, and purifying the residue by silica gel column chromatography with elution system C.

[0501] Second step

[0502] 2-(benzyloxy)cyclobutan-1-ol 6c

[0503] Compound 6b (20.4 g, 115.7 mmol) was dissolved in tetrahydrofuran (200 mL), replaced with nitrogen three times, cooled to -78 °C, and 1 M lithium tri-sec-butylborohydride in tetrahydrofuran (127.3 mL) was added dropwise, the temperature was stirred for 1 hour, then the temperature was allowed to return to room temperature and stirring was continued for 1 hour, the reaction solution was cooled to 0 °C, water (30 mL), 2 M aqueous sodium hydroxide solution (30 mL), and hydrogen peroxide (30 mL) were added in sequence, stirring was continued for 10 minutes after the addition was completed, saturated sodium sulfite solution was added, and extraction was performed with ethyl acetate (150 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to obtain the title compound 6c (a mixture of cis isomers, 18 g, yield: 87.2%).

[0504] Third step

[0505] 2-(2-(benzyloxy)cyclobutoxy)-1,5-difluoro-3-nitrobenzene 6d

[0506] Compound 6c (18.1 g, 101.5 mmol) was dissolved in N,N-dimethylformamide (350 mL), sodium hydride (6.1 g, 152.5 mmol, purity 60%) was added at 0 °C, the temperature was kept and the reaction was stirred for 1 h, 2,3,5-trifluoronitrobenzene (18 g, 101.5 mmol) in N,N-dimethylformamide (60 mL) was added dropwise at -40 °C, the temperature was allowed to return to room temperature and the reaction was stirred for 1 h, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (150 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 6d (a mixture of cis isomers, 27.9 g, yield: 81.9%).

[0507] Fourth step

[0508] 2-(2,4-difluoro-6-nitrophenoxy)cyclobutan-1-ol 6e

[0509] 2-(2,4-difluoro-6-nitrophenoxy) 2,2,2-trifluoroacetate cyclobutyl ester 6f

[0510] Compound 6d (27.9 g, 83.2 mmol) was dissolved in trifluoroacetic acid (100 mL), heated to 80 °C and reacted for 12 h, the reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (100 mL), washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to obtain a mixture of title compounds 6e and 6f (28 g).

[0511] Fifth step

[0512] 6-fluoro-4-nitro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxin 6g

[0513] A mixture of compounds 6e and 6f (28 g) and cesium carbonate (40 g, 123 mmol) were dissolved in N,N-dimethylformamide (200 mL), stirred at 120 °C for 1 h, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 6g (a mixture of cis isomers, 14.5 g).

[0514] Sixth step

[0515] 6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxin-4-amine 6h

[0516] (2aS,8aR)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutene[e][1,4]dioxin-4-amine 6i-1

[0517] (2aR,8aS)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutene[e][1,4]dioxin-4-amine 6i-2

[0518] Compound 6g (14.5 g, 64.4 mmol) was dissolved in tetrahydrofuran (100 mL) and methanol (20 mL), 10% palladium carbon hydrogenation catalyst (wet) (4 g) was added, hydrogen was replaced, the reaction was stirred for 16 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6h (a mixture of cis isomers, 10.5 g, yield: 83.5%).

[0519] MS m / z (ESI): 196.2 [M+1].

[0520] Compound 6h (10.4 g) was separated by chiral column (Shimadzu LC-20AT XR, column: CHIRALPAK IG, 50*250 mm, 10 μm; mobile phase A: acetonitrile, mobile phase B: supercritical carbon dioxide, gradient ratio: A:B=15:85, flow rate: 140 mL / min) to obtain the title compound 6i-1 (4.2 g, yield: 40.3%), 6i-2 (3.97 g, yield: 38.1%).

[0521] Single configuration compound (shorter retention time): 6i-1 (4.2 g, yield: 40.3%)

[0522] Chiral HPLC analysis: retention time 1.735 minutes, purity: 99% (column: ChiralPak IG, 150*3 mm, 5 μm; mobile phase A: acetonitrile, mobile phase B: supercritical carbon dioxide, gradient ratio: A:B=15:85, flow rate: 2 mL / min).

[0523] Single configuration compound (longer retention time): 6i-2 (3.97 g, yield: 38.1%)

[0524] Chiral HPLC analysis: retention time 1.993 minutes, purity: 99% (column: ChiralPak IG, 150*3 mm, 5 μm; mobile phase A: acetonitrile, mobile phase B: supercritical carbon dioxide, gradient ratio: A:B=15:85, flow rate: 2 mL / min).

[0525] Seventh step

[0526] (2aS,8aR)-7-bromo-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutene[e][1,4]dioxepin-4-amine 6j

[0527] Compound 6i-1 (3.2 g, 16.4 mmol) was dissolved in dichloromethane (60 mL), cooled to 0 °C, N-bromosuccinimide (3.91 g, 16.3 mmol) was added in portions, the temperature was kept stirring for 3 hours, the reaction solution was quenched by saturated sodium thiosulfate solution, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5um; mobile phase: water phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to obtain the title compound 6j (1.8 g, yield: 40%).

[0528] MS m / z (ESI): 273.9 [M+1].

[0529] Eighth step

[0530] (2aR,8aS)-7-amino-5-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutene[e][1,4]-dioxepine-4-carboxylic acid methyl ester 6k

[0531] Compound 6j (500 mg, 1.83 mmol) was dissolved in methanol (30 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (134 mg, 183.1 umol), triethylamine (185 mg, 1.82 mmol) were added, carbon monoxide was replaced, the reaction was stirred at 80 °C for 16 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6k (450 mg, yield: 97.4%).

[0532] MS m / z (ESI): 254.3 [M+1].

[0533] Ninth step

[0534] 5-chloro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6l

[0535] Compound 1b (1.5 g, 4.33 mmol) was dissolved in N,N-dimethylacetamide (100 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.97 g, 5.19 mmol) was added, stirred for 10 minutes, compound 5d (714.29 mg, 5.19 mmol) and N,N-diisopropyl ethylamine (1.68 g, 12.97 mmol) were added, and the reaction was stirred for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6l (1.5 g, yield: 80.6%).

[0536] MS m / z (ESI): 430.2 [M+1].

[0537] Tenth step

[0538] (2aR,8aS)-5-Fluoro-7-((7-((4-methoxybenzyl)(methyl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)aminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1,2,2a,8a- tetrahydrobenzo[b]cyclobutane[e][1,4]dioxine-4-carboxylic acid methyl ester 6m

[0539] Compound 6l (300 mg, 697.8 μmol) was dissolved in 1,4-dioxane (20 mL), compound 6k (200 mg, 789.8 μmol) was added, palladium acetate (18 mg, 80.1 μmol), (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (50 mg, 80.2 μmol), cesium carbonate (515 mg, 1.58 mmol) were added, and the reaction was carried out at 100°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6m (500 mg, yield: 97.8%).

[0540] MS m / z (ESI): 647.5 [M+1].

[0541] Tenth step

[0542] (2aR,8aS)-5-Fluoro-7-((7-((4-methoxybenzyl)(methyl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)aminocarbonyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1,2,2a,8a- tetrahydrobenzo[b]cyclobutane[e][1,4]dioxine-4-carboxylic acid 6n

[0543] Compound 6m (300 mg, 463.9 μmol) was dissolved in methanol (5 mL), water (3 mL) and tetrahydrofuran (5 mL), lithium hydroxide monohydrate (185 mg, 4.62 mmol) was added, and the reaction was carried out at 50 °C for 3 hours. After the reaction solution was cooled to room temperature, water was added for dilution, 1M hydrochloric acid was used to adjust the pH to 5-6, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6n (260 mg). The product was used directly in the next reaction without purification.

[0544] MS m / z (ESI): 633.3 [M+1].

[0545] Twelfth step

[0546] 5-(((2aS,8aR)-6-fluoro-7-(4-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidine-1-carbonyl)-1,2,2a,8a- tetrahydrobenzo[b]cyclopenta[e][1,4]dioxin-4-yl)amino)-7-((4-methoxybenzyl)(methyl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6p

[0547] Compound 6n (75 mg, 115.6 μmol) and piperidin-4-one (25 mg, 252.2 μmol, Shanghai Biotech) were dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (45 mg, 348.1 μmol) was added, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (88 mg, 231.4 μmol) was added. After stirring for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6o (80 mg, yield: 94.8%).

[0548] MS m / z (ESI): 714.5 [M+1].

[0549] Thirteenth step

[0550] 5-(((2aS,8aR)-7-(4-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidine-1-carbonyl)-1,2,2a,8a- tetrahydrobenzo[b]cyclopenta[e][1,4]dioxin-4-yl)amino)-7-((4-methoxybenzyl)(methyl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6p

[0551] Compound 6o (80 mg, 109.6 µmol), compound 1g (60 mg, 120.6 µmol) were dissolved in methanol (10 mL), sodium acetate (40 mg, 487.6 µmol) was added, after stirring for 30 minutes, sodium cyanoborohydride (27 mg, 451.3 µmol) was added, the reaction was stirred for 6 hours, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 6p (100 mg, yield: 83.1%).

[0552] MS m / z (ESI): 1082.0 [M+1].

[0553] Fifteenth step

[0554] 5-(((2aS,8aR)-7-(4-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidine-1-carbonyl)-6-fluoro-1,2,2a,8a- tetrahydrobenzo[b]cyclobuteno[e][1,4]dioxin-4-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 6

[0555] Compound 6p (100 mg, 92.3 µmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (2 mL) was added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5µm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compound 6 (a pair of diastereoisomer mixture, 23 mg, yield: 26.1%).

[0556] MS m / z (ESI): 961.9 [M+1].

[0557] 1H NMR (500 MHz, CDC13): δ 8.40 (s, 1H), 8.10 (s, 1H), 7.97-7.93 (m, 1H), 7.83-7.79 (m, 1H), 7.71-7.67 (m, 1H), 7.18-7.15 (m, 1H), 7.02-6.99 (m, 1H), 6.91-6.88 (m, 1H), 6.60-6.57 (m, 1H), 6.33-6.32 (m, 1H), 5.44 (s, 1H), 5.38-5.35 (m, 1H), 5.23-5.20 (m, 1H), 4.80-4.74 (m, 2H), 4.61-4.56 (m, 2H), 3.91-3.83 (m, 1H), 3.77 (s, 3H), 3.37-3.35 (m, 3H), 3.25-3.15 (m, 2H), 3.13-3.12 (m, 3H), 3.11-3.09 (m, 3H), 2.99-2.94 (m, 1H), 2.88-2.71 (m, 5H), 2.35-2.22 (m, 6H), 2.19-2.01 (m, 3H), 1.93-1.85 (m, 4H), 1.56-1.51 (m, 2H), 1.34-1.28 (m, 4H).

[0558] Example 7

[0559] 5-((1-(5-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3- carboxamide 7 (one pair of diastereomeric mixture)

[0560] First step

[0561] tert-Butyl 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 7b

[0562] tert-Butyl 2-amino-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate 7a (1 g, 4.2 mmol, Shanghai Hiphy) was dissolved in acetonitrile (40 mL), tert-butyl nitrite (650 mg, 6.3 mmol) was added, oxonitrate (903 mg, 6.3 mmol), lithium bromide (438 mg, 5.0 mmol), the reaction was stirred at 50 °C for 2 hours, the reaction liquid was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by eluent system B to obtain the title compound 7b (630 mg, yield: 49.7%).

[0563] MS m / z (ESI): 302.0 [M + 1].

[0564] Second step

[0565] tert-Butyl 2-(3-amino-2-oxopyridin-l(2H)-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate 7c

[0566] Compound 7b (630 mg, 2.08 mmol), 3-aminopyridine-2-one (300 mg, 2.72 mmol, Shanghai Hiphy) was dissolved in 1,4-dioxane (20 mL), cuprous iodide (80 mg, 420 pmol), potassium carbonate (577 mg, 4.17 mmol), N,N'-dimethylethylenediamine (37 mg, 419.7 pmol) were added, nitrogen was replaced, the reaction was stirred at 100 °C for 16 hours, the reaction liquid was reduced to room temperature, diluted with ethyl acetate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 7c (550 mg, yield: 79.6%).

[0567] Third step

[0568] tert-Butyl 2-(3-((7-((4-methoxybenzyl)(methyl)amino)-3-(((lR,2R)-2- methoxycyclobutyl)aminocarbonyl)pyrazolo[l,5-a]pyrimidin-5-yl)amino)-2-oxopyridin-l(2H)- yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate 7d

[0569] Compound 7c (550 mg, 1.66 mol), compound 6l (365 mg, 849 μmol) were dissolved in 1,4-dioxane (20 mL), palladium acetate (38 mg, 169.2 μmol), 1,1'-binaphthalene-2,2'-diphenylphosphine (104 mg, 167 μmol), cesium carbonate (1.1 g, 3.34 mmol) were added, and the mixture was heated to 100 °C under nitrogen protection for 2 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 7d (540 mg, yield: 44.8%).

[0570] MS m / z (ESI): 725.7 [M+1].

[0571] Fourth step

[0572] N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7e

[0573] Compound 7d (180 mg, 248.3 μmol) was dissolved in dichloromethane (20 mL), and zinc bromide (480 mg, 2.13 mol) was added. The mixture was stirred for 16 h, saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with dichloromethane (10 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 7e (100 mg, yield: 80%).

[0574] MS m / z (ESI): 505.5 [M+1].

[0575] Fifth step

[0576] 5-((1-(5-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-

[0577] carboxamide 7

[0578] Compound 7e (80 mg, 158.5 μmol), N,N-diisopropylethylamine (30 mg, 232.1 μmol) were dissolved in dichloromethane (10 mL), and trichloroacetonitrile (48 mg, 161.7 μmol) was added under ice bath. The reaction was stirred for 0.5 h, and compound 1g (122 mg, 245.3 μmol) was added. The reaction was heated to 50 °C for 1 h. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to give the title compound 7 (a mixture of diastereomers, 17.8 mg, yield: 12.2%).

[0579] MS m / z (ESI): 914.9 [M+1].

[0580] 1 H NMR (500 MHz, CDCl3): δ 8.40-8.38 (m, 2H), 8.12-8.10 (m, 2H), 8.04 (d, 1H), 7.63 (dd, 1H), 7.04-7.01 (m, 2H), 6.92-6.91 (m, 1H), 6.72 (s, 1H), 6.62-6.60 (m, 1H), 6.40 (t, 1H), 6.29-6.28 (m, 1H), 5.49 (s, 1H), 5.38-5.36 (m, 1H), 5.24-5.21 (m, 1H), 4.66 (s, 2H), 4.63-4.58 (m, 1H), 4.27-4.25 (m, 2H), 3.95-3.90 (m, 2H), 3.89-3.84 (m, 4H), 3.78 (s, 3H), 3.39 (s, 3H), 3.14-3.12 (m, 2H), 3.11 (s, 3H), 2.98-2.94 (m, 1H), 2.88-2.85 (m, 1H), 2.82-2.72 (m, 3H), 2.36-2.34 (m, 1H), 2.26-2.23 (m, 2H), 2.19-2.14 (m, 1H), 1.78-1.70 (m, 2H), 1.54-1.48 (m, 2H).

[0581] Biological evaluation

[0582] Test Example 1, TYK2 JH2 and JAK1 JH2 in vitro enzyme binding experiment

[0583] The experiment adopts the method of fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effect of the compound on TYK2 JH2 and JAK1 JH2 pseudokinase. In this experiment, TYK2 JH2 or JAK1 JH2 pseudokinase can be combined with a fluorescently labeled Tracer and a Tb antibody at the same time, and the Tb antibody acts as a fluorescent donor to produce 495 nm wavelength fluorescence under the action of a certain wavelength excitation light. The Tracer acts as a fluorescent acceptor and can only receive 495 nm wavelength fluorescence to produce 520 nm wavelength fluorescence when it is close enough to the Tb antibody, that is, the fluorescence resonance energy transfer signal. When the compound competes with the Tracer to bind to the pseudokinase JH2 region, the TR-FRET signal is weakened due to the reduction of Tracer binding, and the 520 nm / 495 nm signal ratio can reflect the strength of the inhibitory activity of the compound to the pseudokinase.

[0584] 1. Experimental reagents and instruments

[0585] • Micro pipetting instrument: Echo (LABCYTE Echo550)

[0586] • Enzyme marker: Envision2105 (Perkin Elmer)

[0587] • Constant temperature incubator: CIMO, SPX-60BS-II

[0588] • Thermo MATRIX multichannel pipette: Thermo Fisher, 2-125 μL

[0589] • Centrifuge: Thermo Centrifuge ST 40R

[0590] • Pure water instrument: Millipore Milli-Q Reference system

[0591] • Ultra-low temperature freezer: Haier ultralow temperature freezer

[0592] • Refrigerator: Haier 4 degree freezer; Haier-20 degree freezer

[0593] 2. Experimental method

[0594] 2.1. Preparation of 1× experimental working solution

[0595] 2.2. The experimental operation is as follows:

[0596] 2.2.1. Dissolve compounds to 10 mM stock concentration in DMSO.

[0597] 2.2.2. Prepare 200 times final concentration of compound in different concentration gradient in compound dilution plate, and transfer to Echo plate.

[0598] 2.2.3. Transfer 75 nL of compound from Echo plate to 384 experimental plate by Echo instrument.

[0599] 2.2.4. Add 5 μL 3 times final concentration (0.5 nM as final concentration) of TYK2 JH2 and JAK1 JH2 pseudo kinase to 384 well experimental plate respectively, centrifuge at 1000 rpm for 30 seconds.

[0600] 2.2.5. Add 5 μL 3 times final concentration (1 x as final concentration) of Tb antibody to 384 well experimental plate respectively, centrifuge at 1000 rpm for 30 seconds.

[0601] 2.2.6. Add 5 μL 3 times final concentration (final concentration: 1 nM for TYK2 JH2, 30 nM for JAK1 JH2 respectively) of Tracer to 384 well experimental plate respectively, centrifuge at 1000 rpm for 30 seconds.

[0602] 2.2.7. Incubate at room temperature for 60 minutes, incubate at 4°C overnight.

[0603] 2.2.8. Read the fluorescence signal ratio of 520 nm / 495 nm by Envision microplate reader (PerkinElmer).

[0604] 3. Data analysis

[0605] XLfit, a software written by IDBS company, integrated in Microsoft Excel environment, was used for data processing and analysis. First, the average values of high signal control and low signal control were calculated respectively, then the inhibition rate of each compound well was calculated according to the formula "Inhibition rate of single well % = 100- (average value of high signal control- signal value of single well) / (average value of high signal control- average value of low signal control)". Then the concentration and corresponding inhibition rate data were imported into XLfit software, and the Dose Response One Site 205 model in the software was used to fit the four-parameter inhibition rate-concentration curve, and the IC 50 value of the compound was calculated.

[0606] Table 1 IC50 of TYK2 JH2 and JAK1 JH2 pseudo kinase binding inhibition activity 50

[0607] Conclusion: The compounds of the present disclosure have significant inhibitory effect on TYK2-JH2 pseudokinase.

[0608] Test Example 2, Inhibition of HeLa Cell IFNα-induced STAT1 Protein Phosphorylation by Compounds of the Present Disclosure

[0609] The inhibitory effect of the compounds of the present disclosure on HeLa cell IFNα-induced STAT1 protein phosphorylation was detected by the method of AlphaLISA, and the details are as follows:

[0610] 1.1 Reagents and Instruments

[0611] 1.1.1 Reagents

[0612] 1.1.2 Instruments

[0613] 1.2 Cells and Culture Method

[0614] HeLa cells were purchased from the American Type Culture Collection (ATCC), and MEM medium (10% FBS) was used for culture at 37°C in a 5% carbon dioxide incubator, with 2-3 passages per week.

[0615] 1.3 Compound Preparation

[0616] a. The test compound was dissolved in DMSO to 0.5 mM.

[0617] b. The starting concentration of the compound was 0.5 mM, with 3-fold dilution, and 10 concentration gradients.

[0618] c. All concentrations of the compound were diluted 50-fold with culture solution for standby use.

[0619] 4. Experimental Procedure

[0620] a. Cell counting, adjusting the cell density to 5 x 10 5 / mL with fresh culture solution.

[0621] b. 96 Well Black Polystyrene Microplate, 80 μL of cells were inoculated per well, and incubated at 37°C for 4 hours.

[0622] c. Add 10 μL of compound to each well (add 10 μL of 0.5% DMSO to columns 1 and 12), and incubate at 37°C for 1 hour.

[0623] d. Prepare 100 ng / mL of IFNα with culture solution, add 10 μL of IFNα to each well (add 10 μL of culture solution to column 1 as a control), and incubate at 37°C for 15 minutes.

[0624] e. Prepare lysis solution according to AlphaLISA SureFire Ultra STAT1 pY701 kit instruction. Remove cell culture supernatant, add 50 μL lysis solution per well, shake to lyse at room temperature for 15 minutes.

[0625] f. Prepare Acceptor Mix according to AlphaLISA SureFire Ultra STAT1 pY701 kit instruction. Add 5 μL of Acceptor Mix per well in 96-well low volume white plate.

[0626] g. Transfer 10 μL cell lysate to 96-well low volume white plate, centrifuge, incubate at room temperature for 1 hour.

[0627] h. Prepare Donor Mix according to AlphaLISA SureFire Ultra STAT1 pY701 kit instruction. Add 5 μL Donor Mix per well, incubate at room temperature overnight in the dark.

[0628] i. Read plate detection with PHERASTAR HS Microplate reader.

[0629] j. Graphpad software plot, calculate IC 50 value of the compound of the present disclosure.

[0630] Table 2 Inhibition activity of the compound of the present disclosure on STAT1 protein phosphorylation induced by IFNα in HeLa cells

[0631] Conclusion: The compound of the present disclosure has good inhibitory effect on STAT1 protein phosphorylation induced by IFNα in HeLa cells.

[0632] Test Example 3, Experiment of the compound of the present disclosure inhibiting IP10 production induced by IFNα in human whole blood

[0633] Fresh whole blood was collected using heparin anticoagulant tubes. Whole blood was added to 96-well round bottom plates at a volume of 180ul per well. Cells were treated with 10ul of media containing different concentration gradient of compounds (DMSO final concentration was 0.5%) per well and duplicates were set up, and incubated in 37 degree incubator for 60min. 10ul of IFN-a (final concentration was 20ng / ml) was added per well, and blank media was used as negative control. Incubated in 37 degree incubator for about 24h. After 24h, supernatant was collected: the cell plate was taken out of 37 degree incubator, centrifuged at 2000rpm / min for 5min, 80ul of supernatant was transferred to a new 96-well round bottom plate per well, sealed with tin foil, and stored in -80 degree freezer until tested. Human IP-10 / CXCL10 ELISA kit from eBioscience was used to test IP10 in supernatant by ELISA.

[0634] A standard curve was plotted according to the standard, and the corresponding calculation formula Y=aX+b was obtained, R squared>0.99. Wherein Y value represents OD450 value, X represents IP10 concentration. The IP10 concentration corresponding to each OD450 value was calculated. The final concentration was 100X (pg / ml). The IFN-a stimulation + DMSO treatment well was used as the positive control well, and the IFN-a unstimulated + DMSO treatment well was used as the negative control well. The inhibition rate was: (positive control well - test compound) / (positive control well - negative control well) * 100%.

[0635] Graphpad software was used to plot the inhibition curve according to the compound concentration point and the corresponding inhibition rate, and the compound concentration when the inhibition rate was 50% was calculated, that is, IC 50 value.

[0636] Table 3 IC 50 values of the compounds of the present disclosure for inhibiting IFNα-induced production of IP10 by human whole blood

[0637] Conclusion: The compounds of the present disclosure have obvious inhibitory activity on IFNα-induced production of IP10 by human whole blood.

[0638] Test Example 4. Degradation activity of the compounds of the present disclosure on TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells.

[0639] TYK2 is localized in the cytoplasm and involved in the signaling of multiple cytokines. OCI-LY3 is a human diffuse large B-cell lymphoma cell line with high expression of TYK2, and TYK2 is involved in the signaling of IL-10 and other cytokines in this cell. In this experiment, the degradation rate of TYK2 in the cells treated with compounds was detected by hypersensitive electrochemiluminescence technology (Meso Scale Discovery, MSD) to evaluate the degradation activity of the compounds on intracellular TYK2. The cells were prepared into a cell suspension with a cell density of 5E5 / mL with medium (RPMI1640, Merck PWL015; containing 20% FBS, Gibco 10091-14; containing 55 μM mercaptoethanol, Gibco 31350010), and added to a 96-well cell culture plate (Corning, 3599) at a volume of 196 μL per well. Incubation was performed in a 37-degree, 5% CO2 cell incubator. Then, the cell culture medium containing 4-fold concentration gradient dilution of the compound was added to the experimental wells at 4 μL per well, or the medium containing DMSO (final concentration 0.1%) was added to the positive and negative control wells at 4 μL per well. The cell culture plate was mixed by shaking at 300 rpm for 5 minutes, and incubated in a 37-degree, 5% CO2 cell incubator for 24 hours. The incubated cell culture plate was centrifuged at 400g for 5 minutes, and the supernatant was discarded to obtain the cell pellet. Then, 45 μL of 1x lysis buffer (revvity, ALSU-LB-100ML) was added to each well, and the mixture was shaken at room temperature for 5 minutes and then ultrasonically lysed for 5 minutes. Finally, the mixture was centrifuged at 2000g for 5 minutes, and the supernatant was collected as the cell lysate sample. A MSD 96-well plate (MSD, L15XA-6) was coated with 50 μL of PBS buffer containing 1 μg / mL TYK2 antibody (Santa Cruz, sc-5271) per well one day in advance, and incubated at 4 degrees overnight. During the MSD experiment, the coating solution was discarded, 150 μL of phosphate buffer containing 5% BSA was added to each well for blocking for 1 hour. The plate was washed 3 times with PBS+0.05% Tween20 washing solution, 25 μL of cell lysate sample or TYK2 standard (BPS Bioscience, 100400) was added to each well, and the mixture was shaken at 500 rpm for 1.5 hours. After discarding the sample, the plate was washed 3 times. 25 μL of phosphate buffer containing 0.75 μg / mL TYK2 antibody (CST, 9312) was added, and the mixture was shaken at 500 rpm for 1 hour. After discarding the primary antibody, the plate was washed 3 times. 25 μL of buffer containing 1 μg / mL SULFO-TAG labeled anti-rabbit secondary antibody (MSD, R32AB-1) was added, and the mixture was shaken at 500 rpm for 1 hour in the dark. After discarding the secondary antibody, the plate was washed 3 times, 150 μL of 1x MSD Read buffer (MSD, R92TC-2) was added to each well, and the signal value was read by MESO SECTOR S600.The rate of change of the experimental well reading relative to the DMSO control well reading is the degradation rate. Then, using Graphpad Prism software, the degradation curve is plotted according to the concentration of each compound and the corresponding degradation rate, and the concentration of the compound when the degradation rate reaches 50%, i.e. DC, is calculated. 50 Values.

[0640] Table 4 DC of the compounds of the present disclosure in degrading TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells 50 Values

[0641] Conclusion: The compounds of the present disclosure have obvious degradation activity on TYK2 in OCI-LY3 human diffuse large B-cell lymphoma cells.

[0642] Test Example 5: Inhibition effect of the compounds of the present disclosure on pSTAT3 in IFNa-induced human T lymphocytes

[0643] The frozen human PBMCs were resuscitated with RPMI 1640 complete growth medium containing 10% inactivated FBS. The T cells in the PBMCs were sorted according to the T cell sorting kit and cultured overnight. The overnight cultured T cells were inoculated in a 96-well plate at 1 x 10 5 cells / well. The cells were treated with serially diluted compounds and cultured in a 37°C & 5% CO2 incubator for 1 hour. The final concentration of IFNa was added to 200 ng / mL, and the cells were cultured in a 37°C & 5% CO2 incubator for 30 minutes. Then the treated cells were lysed, and the level of phosphorylated STAT3 in the cells was measured by an Elisa kit according to the manufacturer's instructions. The inhibition data was calculated by comparing with the 0% inhibition of the IFNa / DMSO control well and the 100% inhibition of the non-stimulated control well. Then a dose-response curve was generated to determine the concentration required to inhibit 50% of the cell response (IC 50 ), which was obtained by non-linear regression analysis using GraphPad Prism.

[0644] Conclusion: The compounds of the present disclosure have an inhibitory effect on TYK2-mediated, IFNa-induced STAT3 phosphorylation in human T lymphocytes.

[0645] Test Example 6: Inhibition effect of the compounds of the present disclosure on IL-12 / IL-18-induced IFN-γ production in human PBMC cells

[0646] Fresh PBMC cells were centrifuged (300g / min, 10min) and the supernatant was discarded. The cell pellet was resuspended by adding fresh culture medium and counting. The cell density was prepared to be 6.66E5 / ml cell suspension and mixed well. 150ul volume was added to each well of a 96-well round bottom plate. The plate was placed in a 37-degree incubator. The compound was prepared to be 20mM stock solution with DMSO, then 10-fold dilution was performed in a 96-well round bottom plate, to be 2mM as the first concentration, and then 4-fold dilution was performed with DMSO in sequence, totally 9 concentration points, and DMSO blank well was used as blank control. The resulting compound DMSO solution was further diluted by 25 times: 6ul DMSO compound solution was added to 144ul fresh culture medium, and mixed well on a plate shaker for 10min. 25ul / well was added to the cell plate, and the DMSO final concentration was 0.5%. The plate was incubated in a 37-degree incubator for 30min. The IL-12 stock solution (200ug / ml) was diluted by 12500 times, and the IL-18 stock solution (100ug / ml) was diluted by 1250 times, and then mixed well in a 1:1 volume ratio. 25ul volume was added to each well of the cell plate, and the final concentration of IL-12 was 1ng / ml, and the final concentration of IL-18 was 5ng / ml. The blank medium was used as negative control. The plate was incubated in a 37-degree incubator for about 24h. After 24h, the supernatant was collected: the cell plate was taken out from the 37-degree incubator, centrifuged at 2000rpm / min for 5min, and 100ul supernatant was transferred to a new 96-well round bottom plate for ELISA kit detection of IFN-γ.

[0647] The IL-12 / IL-18 stimulation + DMSO treatment well was used as the positive control well, and the unstimulated + DMSO treatment well was used as the negative control well. The inhibition rate was: (positive control well - test compound) / (positive control well - negative control well) * 100%. The Graphpad software was used to draw the inhibition curve according to the compound concentration points and the corresponding inhibition rate, and the compound concentration when the inhibition rate was 50% was calculated as IC 50

[0648] Conclusion: The compound of the present disclosure has good inhibitory activity on IL-12 / IL-18 induced IFN-γ.​

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof: in: G 1 Selected from N, NR 0 , O, S and CR'; G 2 N or C; G 3 N or C; Z 1 selected from C(O)NR 1 R 2 、C(O)NR 1a OR 2 、C(O)NR 1a NR 1 R 2 、NR 1a C(O)NR 1 R 2 、C(O)C(O)NR 1 R 2 、C(O)R 2 、C(=NR 1a )NR 1 R 2 、S(O) r R 2 、S(=NR 1a )R 2 and S(=NR 1a )(O)R 2 ; R 4 、R 5 、R 0 and R 1a The same or different, and each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyl, OR 12 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by; R 1 and R 2 are the same or different and are each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, OR 12 NR 10 R 11 、C(O)NR 10 R 11 NR 13 C(O)R 12 、C(O)R 12 、C(O)OR 12 、OC(O)R 12 、S(O) r R 12 、S(O) r NR 10 R 11 , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 Replaced by; or R 1 、R 2 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R 01 replaced by; R 10 、R 11 、R 12 and R 13 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 21 R 22 、C(O)NR 21 R 22 NR 23 C(O)R 24 、C(O)R 24 、C(O)OR 24 、OC(O)R 24 、S(O) r R 24 、S(O) r NR 21 R 22 , OR 24 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by; or R 10 、R 11 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R 01 replaced by; R 3 、R 6 and R' are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 21 R 22 、C(O)NR 21 R 22 、C(O)R 24 、C(O)OR 24 、S(O) r R 24 、S(O) r NR 21 R 22 , OR 24 、C(=NR 23 )R 24 、S(=NR 23 )R 24 、S(=NR 23 )(O)R 24 、P(O)R 21 R 22 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 02 replaced by; L 1 、L 3 、L 4 、L 5 and L 6 are the same or different and are each independently selected from a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C(O), C(O)N(R L )、N(R L )C(O), S(O) r 、S(O) r N(R L )、N(R L )S(O) r 、N(R L ), S(=NR 23 ), S(=NR 23 )(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl and heteroaryl; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replaced by; L 2 is selected from the group consisting of a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), C(O)-heterocyclyl, heterocyclyl-C(O), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, heterocyclyl-heterocyclyl, aryl, heteroaryl, and cycloBZ 2 - Ring B1; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, Ring B1 and Ring B are each independently optionally substituted by one or more R 03 replaced by; Ring B1 is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Z 2 selected from the group consisting of a bond, O, S, O-alkylene, alkylene-O, C(O), C(O)-alkylene, alkylene-C(O), alkylene, N(R L )、S(O) r 、S(=NR 23 ), S(=NR 23 )(O), cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replaced by; Each R 01 、R 02 、R 03 and R 04 are the same or different and are each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 21 R 22 、C(O)NR 21 R 22 NR 23 C(O)R 24 NR 23 C(O)NR 21 R 22 、C(O)R 24 、C(O)OR 24 、OC(O)R 24 、S(O) r R 24 、S(O) r OR 24 、S(O) r NR 21 R 22 NR 23 S(O) r R 24 、C(=NR 23 )R 24 、S(=NR 23 )R 24 、S(=NR 23 )(O)R 24 、P(O)R 21 R 22 , OR 24 、=CR 15 R 16 、=NR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R * replaced by; or two R 03 and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R * replaced by; R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 21 R 22 、C(O)NR 21 R 22 、C(O)R 24 、S(O) r R 24 、S(O) r NR 21 R 22 , OR 24 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; or R 15 、R 16 and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * replaced by; R 21 、R 22 、R 23 、R 24 and R L are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 30 R 31 、C(O)NR 30 R 31 NR 33 C(O)R 32 、C(O)R 32 、C(O)OR 32 、OC(O)R 32 , OR 32 、S(O) r R 32 、S(O) r NR 30 R 31 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally replaced by one or more R * replaced by; R 30 、R 31 、R 32 and R 33 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, and heteroaryl; E is selected from: is a single bond or a double bond; Q 1 , Q 2 , Q 3 , Q 4 and Q 5 One of them is a carbon atom and L 6 connection, the others are each independently selected from N, CH and CR q ; Each R q are the same or different and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 21 R 22 、C(O)NR 21 R 22 、C(O)R 24 、C(O)OR 24 、S(O) r R 24 、S(O) r NR 21 R 22 , OR 24 、C(=NR 23 )R 24 、S(=NR 23 )R 24 、S(=NR 23 )(O)R 24 、P(O)R 21 R 22 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 04 replaced by; or two R q and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 04 replaced by; R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more R * replaced by; Y 1 N or CR Y1 ; Y 2 CR Y2 R Y4 or C(O); Y 3 N or CR Y3 ; R Y1 、R Y2 、R Y3 and R Y4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group and a heterocyclic group; the alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group and heterocyclic group are each independently optionally replaced by one or more R * replaced by; or, R Y2 、R Y4 and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * replaced by; Each R * are the same or different and are each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, alkylthio, amino, -NHalkyl, -N(alkyl), -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl), amido, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl; Each r is the same or different and is independently 0, 1 or 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt thereof: in, s is 0, 1, 2, or 3; L 1 To L 6 、R 1a 、R 1 to R 7 and R q As defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 1 A hydrogen atom or C 1-6 Alkyl, R 2 Selected from hydrogen atoms, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group, wherein the 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group are each independently optionally substituted by one or more R 01 Replaced, or R 1 、R 2 and the nitrogen atom to which it is attached together form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted by one or more R 01 Replaced by; R 01 As defined in claim 1; and / or L 1 is a bond or NH; and / or L 2 Selected from Preferred u is 1, 2, 3 or 4; Q and L are the same or different and are each independently selected from a bond, (CR g R h ) q 、(CR g R h ) q O、O(CR g R h ) q NR i , O and S; R g and R h are the same or different and are each independently a hydrogen atom or R 03 , R i is a hydrogen atom or an alkyl group; n is 0, 1, 2 or 3; b is 0, 1, 2 or 3; a is 0, 1 or 2; q is 0, 1 or 2; R 03 As defined in claim 1; and / or L 6 -L 5 -L 4 -L 3 for U is selected from N, CH and CR 03 , V is selected from N, CH and CR 03 ; c is 0, 1 or 2; d is 0, 1 or 2; e is 0, 1 or 2; f is 1 or 2; v is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4; R 03 As defined in claim 1; and / or each R q are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or R 3 is a hydrogen atom, and / or R 6 is a hydrogen atom, and / or R 4 is a hydrogen atom, and / or R 5 C 1-6 alkyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

5. A compound represented by general formula (IA), or a salt thereof: in, R P is an amino protecting group, preferably PMB; Z 1 , G 1 , G 2 , G 3 、L 1 To L 6 , E, R 3 、R 5 and R 6 As defined in claim 1.

6. A compound, or a salt thereof, selected from any of the following structures:

7. A method for preparing the compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IA) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt; Among them, R P is an amino protecting group, preferably PMB; R 4 is a hydrogen atom; Z 1 , G 1 , G 2 , G 3 、L 1 To L 6 , E, R 3 、R 5 and R 6 As defined in claim 1.

8. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Use of the compound represented by general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a TYK2 inhibitor and / or degrader.

10. Use of a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for treating and / or preventing autoimmune diseases, inflammatory diseases and cancer; preferably in the preparation of a medicament for treating and / or preventing psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, palmoplantar pustulosis, Sjögren's syndrome, ulcerative colitis, alopecia areata, hidradenitis suppurativa, immune disorders, posterior uveitis, panuveitis, dermatomyositis, cicatricial alopecia and asthma.

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