CN118344365A

CN118344365A - Condensed heteroaryl compound, preparation method and medical application thereof

Info

Publication number: CN118344365A
Application number: CN202410061321.6A
Authority: CN
Inventors: 李心; 董怀德; 白东栋; 陈一千; 贺峰
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2023-01-16
Filing date: 2024-01-16
Publication date: 2024-07-16

Abstract

The present disclosure relates to fused heteroaryl compounds, methods of making and their use in medicine. In particular, the present disclosure relates to a fused heteroaryl compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof as a therapeutic agent, particularly as a TYK2 inhibitor and in the preparation of a medicament for treating and/or preventing TYK 2-mediated or dependent diseases or conditions.

Description

Condensed heteroaryl compound, preparation method and medical application thereof

Technical Field

The present disclosure belongs to the field of medicine, and relates to a condensed heteroaryl compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application thereof as a therapeutic agent, particularly application as a TYK2 inhibitor and application in preparation of a medicament for treating and/or preventing TYK 2-mediated or dependent diseases or symptoms.

Background

Cytokine signaling plays a key role in controlling immune cell growth, differentiation, function and communication. Receptor-binding Janus kinases (JAKs) mediate a variety of cytokine signaling pathways through the action of signal transduction and transcription activators (STATs).

JAK family members, including JAK1, JAK2, JAK3 and TYK2, are non-receptor tyrosine protein kinases related to cytokine receptors, JAK molecules are activated and phosphorylate receptor tyrosine residues to act as docking sites upon stimulation and oligomerization of these receptors for subsequent STAT protein recruitment and phosphorylation. Conversely, phosphorylated STAT proteins dimerize, translocate to the nucleus and activate transcription of genes that mediate cytokine-induced responses. These cytokine mediated JAK/STAT pathways are tightly regulated and dysfunctional JAK/STAT activities have been demonstrated as markers of many immune and autoimmune diseases, inflammatory diseases, and cellular transformations.

Tyrosine kinase 2 (TYK 2) is the first identified member of the JAK family, 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, with a common p40 subunit), the type I Interferon (IFN) family, and the IL-6 and IL-10 families. TYK 2-mediated cytokine signaling plays a key role in the pathogenesis of autoimmune and inflammatory diseases. In particular, IL-23 (heterodimer containing p40 and p19 subunits) is critical for the differentiation and proliferation of T helper cells 17 (Th 17), which are key participants (Aggarwal,S et al.,"Interleukin-23promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17"J Biol Chem.2003,278:1910-1914). of several autoimmune diseases and IL-12, consisting of p40 and a unique p35 subunit, plays an important role in regulating Th1 development and IFN-gamma secretion by these cells. IL-12 and IL-23 play an important role in a variety of inflammatory diseases [ e.g., psoriasis (Ps), lupus, inflammatory Bowel Disease (IBD), multiple Sclerosis (MS), rheumatoid Arthritis (RA) ] by mediating Th1/Th17 responses, and the like. For example, in a mouse model, it was found that blocking or deleting the common subunit P40 of IL-12 and IL-23 or the common receptor IL23R protects mice from various autoimmune diseases (psoriasis, lupus, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, etc.). In human disease, high levels of IL-12 and IL-23 are observed in the diseased skin of psoriatic patients, and then the levels decline after various treatments for psoriasis. In addition, monoclonal antibodies that block IL-12/IL-23 common subunit p40 (Ustekinumab, briakinumab, etc.) or IL-23 specific subunit p19 (Tildrakizumab, risankizumab, etc.) have been shown to have clinical efficacy in the treatment of psoriasis, crohn's disease, etc. Meanwhile, I type IFN family members (IFN-alpha, -beta, -epsilon, -kappa, -omega and the like) which act through heterodimeric IFN receptor (IFNAR) are important media for innate immunity and adaptive immunity, and can activate various elements in immune response and enhance expression and release of autoantigens, so that the I type IFN family members become key participants for amplification of autoimmune diseases. The importance of type I IFNs in the pathogenesis of Systemic Lupus Erythematosus (SLE) has been demonstrated experimentally, with elevated serum ifnα levels found in many patients and elevated expression of type I IFN-regulatory genes in Peripheral Blood Mononuclear Cells (PBMCs) and affected organs in human SLE patients. In addition, other studies have reported that activation of type I interferon is closely related to the extent of SLE disease.

Several studies have demonstrated the importance of TYK2 in the pathogenesis of the autoimmune diseases described above. For example, rodents that have TYK2 inactivated or chemically inhibited in vivo have been found to exhibit disease resistance in experimental autoimmune disease models such as psoriasis, multiple sclerosis and inflammatory bowel disease. Crowd studies have found that SLE is reduced in children and adults carrying TYK2 activity deletion variants (e.g., rs12720356 and rs 34536443) in the mexico Mestizo population. Several activity-deficient variants of TYK2 were found by whole genome association studies (GWAS) to be significantly associated with resistance to inflammatory diseases, including multiple sclerosis, psoriasis, crohn's disease, lupus and rheumatoid arthritis, further demonstrating that TYK2 has an important role in a broad range of autoimmune diseases.

It follows that there is a potential therapeutic benefit in developing drugs that inhibit the action of TYK 2-mediated cytokine signaling pathways against human autoimmune diseases. Indeed, the highly selective allosteric TYK2 inhibitor BMS986165 has been shown to effectively block IL-12/IL-23 and type I IFN signaling pathways, thus exhibiting significant efficacy in a variety of experimental autoimmune disease models (psoriasis, SLE and IBD). In addition, the clinical test results in phase 2 report that the medicine achieves the main curative effect endpoint in patients with moderate to severe plaque psoriasis, and has good risk benefit ratio. Most patients had a decrease in psoriasis area and severity index score of more than 75% (PASI 75) and some patients had a decrease in PASI score of more than 90% (PASI 90) after 986165 12 weeks of BMS administration, further demonstrating the efficacy and potential of TYK2 as a target in the field of autoimmune disease treatment.

Patent applications for published TYK2 inhibitors include WO2014074661A1、WO2020086616A1、WO2020092196A1、WO2020156311A1、WO2019023468A1、WO2020163778A1、WO2020081508A1、WO2021092246A1、WO2021162942A1 et al.

Disclosure of Invention

The invention aims to provide a compound shown in a general formula (I), or pharmaceutically acceptable salt thereof:

wherein:

G is N or CR ¹;

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl and heteroaryl;

R ⁴、R⁵ and R ⁷ are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group; the alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more R ⁰¹;

R ¹、R³ and R ⁶ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cyano, nitro 、NR²⁰R²¹、C(O)NR²⁰R²¹、NR²²C(O)R²³、NR²²C(O)NR²⁰R²¹、C(O)R²³、C(O)OR²³、OC(O)R²³、S(O)_rR²³、S(O)_rOR²³、OS(O)_rR²³、S(O)_rNR²⁰R²¹、NR²²S(O)_rR²³、C(＝NR²²)R²³、S(＝NR²²)(O)R²³、OR²³、 cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more R ⁰²;

Each R ² and R ⁸ are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cyano, nitro 、NR²⁴R²⁵、C(O)NR²⁴R²⁵、NR²⁶C(O)R²⁷、NR²⁶C(O)NR²⁴R²⁵、C(O)R²⁷、C(O)OR²⁷、OC(O)R²⁷、S(O)_rR²⁷、S(O)_rOR²⁷、OS(O)_rR²⁷、S(O)_rNR²⁴R²⁵、NR²⁶S(O)_rR²⁷、C(＝NR²⁶)R²⁷、S(＝NR²⁶)(O)R²⁷、OR²⁷、 cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more R ⁰³;

Each R ⁰¹、R⁰² and R ⁰³ are the same or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, cyano, alkenyl, alkynyl, NR ^aR^b、C(O)NR^aR^b, alkylene NR ^aR^b, alkylene C(O)NR^aR^b、NR^cC(O)R^d、NR^cC(O)NR^aR^b、C(O)R^d、C(O)OR^d、OC(O)R^d、S(O)_rR^d、S(O)_rOR^d、OS(O)_rR^d、S(O)_rNR^aR^b、NR^cS(O)_rR^d、C(＝NR^c)R^d、S(＝NR^c)(O)R^d、OR^d、 nitro, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, aryloxy, and heteroaryloxy; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, aryloxy, and heteroaryloxy are each independently optionally substituted with one or more R;

Each of R ²⁰、R²¹、R²²、R²⁴、R²⁵、R²⁶、R^a、R^b and R ^c is the same or different and is each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, and heterocyclyl; each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is independently optionally substituted with one or more R;

Or, R ^a、R^b and the nitrogen atom to which it is attached together form a heterocyclic group, or R ²⁰、R²¹ and the nitrogen atom to which it is attached together form a heterocyclic group, or R ²⁴、R²⁵ and the nitrogen atom to which it is attached together form a heterocyclic group; each of the heterocyclic groups formed is independently optionally substituted with one or more R;

Each of R ²³、R²⁷ and R ^d is the same or different and is each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more R;

Each R is the same or different and is each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, cyano, alkenyl, alkynyl, amino, amido, alkylene amino, alkylene amido, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl;

each r is the same or different and is each independently 0,1 or 2;

n is 0,1, 2, 3, 4,5, 6, 7 or 8; and, in addition, the method comprises the steps of,

M is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: g is N.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 14 membered aryl; preferably, ring A isS is 0, 1, 2, 3 or 4; most preferably, ring A is

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 14 membered aryl or a5 to 14 membered heteroaryl; preferably, ring a is a 6 to 14 membered aryl or a5 or 6 membered heteroaryl;

More preferably, ring A is Or pyridonyl, s is 0, 1,2, 3 or 4; most preferably, ring A isIn some embodiments, ring a is To NR ⁷, a bond with x is to R ⁸.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is

Q ¹ and Q ² are the same or different and are each independently selected from CR ^jR^k、NR^m, O and S;

Each R ^j and R ^k is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cyano, nitro 、NR²⁴R²⁵、C(O)NR²⁴R²⁵、NR²⁶C(O)R²⁷、NR²⁶C(O)NR²⁴R²⁵、C(O)R²⁷、C(O)OR²⁷、OC(O)R²⁷、S(O)_rR²⁷、S(O)_rOR²⁷、OS(O)_rR²⁷、S(O)_rNR²⁴R²⁵、NR²⁶S(O)_rR²⁷、C(＝NR²⁶)R²⁷、S(＝NR²⁶)(O)R²⁷、OR²⁷、 cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more R ⁰³;

or, R ^j、R^k and the carbon atom to which it is attached form c=o, cycloalkyl, or heterocyclyl, each of which is independently optionally substituted with a substituent selected from R ⁰³;

R ^m is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group; the alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more R ⁰³;

R ⁰ is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkenyl, alkynyl 、NR²⁴R²⁵、C(O)NR²⁴R²⁵、NR²⁶C(O)R²⁷、NR²⁶C(O)NR²⁴R²⁵、C(O)R²⁷、C(O)OR²⁷、OC(O)R²⁷、S(O)_rR²⁷、S(O)_rOR²⁷、OS(O)_rR²⁷、S(O)_rNR²⁴R²⁵、NR²⁶S(O)_rR²⁷、C(＝NR²⁶)R²⁷、S(＝NR²⁶)(O)R²⁷、 cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with 1, 2, 3, or 4R ⁰³;

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

R ²⁴、R²⁵、R²⁶、R²⁷、R⁰³ and R are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: when ring A is a pyridonyl group, the group attached to the nitrogen atom is not halogen.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Is that

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

r ⁸、R²⁴、R²⁵、R²⁶、R²⁷、R⁰³ and R are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Is that Preferably, the method comprises the steps of,Is that

S is 0, 1,2, 3 or 4; n is 0, 1,2 or 3; q is 0, 1,2 or 3;

R ^8a is R ⁸,R^8b is a hydrogen atom or R ⁸;R⁸ is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or (III) or a pharmaceutically acceptable salt thereof, wherein: r ⁰ is selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a 3 to 10 membered cycloalkyl group, a 3 to 10 heterocyclyl group, a 6 to 10 membered aryl group, and a 5 to 14 membered heteroaryl group, each of which is independently optionally substituted with 1, 2,3, or 4 substituents selected from the group consisting of halogen, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, and C _1-6 haloalkoxy group; preferably, R ⁰ is selected from the group consisting of 3-to 10-membered cycloalkyl, 3-to 10-heterocyclyl, 6-to 10-membered aryl, and 5-to 14-membered heteroaryl, each of said 3-to 10-membered cycloalkyl, 3-to 10-heterocyclyl, 6-to 10-membered aryl, and 5-to 14-membered heteroaryl independently being optionally substituted with 1, 2,3, or 4 substituents selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; further preferably, R ⁰ is 6 membered heteroaryl; more preferably

In some embodiments of the present disclosure, the compound of formula (I) or (IV) or a pharmaceutically acceptable salt or fragment thereof (A2), wherein: each R ^8a is the same or different and is each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxy, and 3 to 6 membered heterocyclyl;

R ^8b is selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxy, and 3 to 6 membered heterocyclyl;

In some embodiments, each R ^8a is the same or different and is each independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; r ^8b is selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound of formula (I) or (IV) or a pharmaceutically acceptable salt or fragment thereof (A2), wherein: r ^8b is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

Wherein,

s is 0,1, 2, 3 or 4; n is 0,1, 2 or 3;

the rings B, R ² to R ⁸、R²⁴、R²⁵、R²⁶、R²⁷、R⁰³, R and m are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment (a 1), (a 2) thereof, wherein: q ¹ is O, Q ² is O or CR ^jR^k,R^j、R^k, together with the carbon atoms to which they are attached, form a 3-to 10-membered cycloalkyl group; preferably, Q ¹ is O and Q ² is O.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (III):

Wherein R ⁰ is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkenyl, alkynyl 、NR²⁴R²⁵、C(O)NR²⁴R²⁵、NR²⁶C(O)R²⁷、NR²⁶C(O)NR²⁴R²⁵、C(O)R²⁷、C(O)OR²⁷、OC(O)R²⁷、S(O)_rR²⁷、S(O)_rOR²⁷、OS(O)_rR²⁷、S(O)_rNR²⁴R²⁵、NR²⁶S(O)_rR²⁷、C(＝NR²⁶)R²⁷、S(＝NR²⁶)(O)R²⁷、 cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with 1,2,3, or 4R ⁰³;

n is 0, 1, 2 or 3;

In some embodiments of the present disclosure, the compound of formula (I) or (III) or a pharmaceutically acceptable salt thereof is a compound of formula (IV):

wherein q is 0,1, 2 or 3;

each R ^8a is the same or different and is each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkenyl, alkynyl, NR ^aR^b、C(O)NR^aR^b, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^8b is selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkenyl, alkynyl, NR ²⁴R²⁵、C(O)NR²⁴R²⁵, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

The rings B, R ² to R ⁷、R^a、R^b、R²⁴、R²⁵ and m are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: ring B is a 3 to 12 membered cycloalkyl or 3 to 12 membered heterocyclyl; preferably selected from More preferably selected from

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: ring B is a nitrogen-containing heterocyclyl; preferably, ring B isRing B' is a nitrogen-containing heterocyclic group.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: ring B is a 4 to 7 membered heterocyclyl; in some embodiments, ring B is selected from pyrrolidinyl, isoxazolidinyl, pyrazolidinyl, 5-oxa-6-azaspiro [2.4] heptanyl, and 5, 6-diazaspiro [2.4] heptanyl; in some embodiments, ring B is a 5 or 6 membered heterocyclyl; in some embodiments, ring B isIn some embodiments, ring B isIn some embodiments, ring B isIn some embodiments, ring B isIn some embodiments, ring B is

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: ring B is cycloalkyl orPreferably, ring B isMore preferably, ring B is

X is CR ^2aR^2b、NR^2g, O and S; p is 0, 1,2, 3 or 4; u is 0, 1 or 2; r ^2a、R^2b、R^2c and R ^2d are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cyano, nitro, NR ²⁴R²⁵, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more R ⁰³; or R ^2c、R^2d together with the carbon atom to which it is attached form c=o, cycloalkyl or heterocyclyl; r ^2g is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group; r ²⁴、R²⁵ and R ⁰³ are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: Is that

Preferably, the method comprises the steps of,Is thatMore preferablyX is CR ^2aR^2b、NR^2g, O and S; p is 0, 1,2, 3 or 4; u is 0, 1 or 2; r ^2a、R^2b、R^2c、R^2d、R^2e and R ^2f are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cyano, nitro, NR ²⁴R²⁵, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more R ⁰³;

r ^2g is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group;

Or R ^2c、R^2d and the carbon atom to which it is attached form c=o, cycloalkyl or heterocyclyl, or R ^2d、R^2e and the carbon atom to which it is attached form =, cycloalkyl or heterocyclyl, or R ^2e、R^2f and the carbon atom to which it is attached form c=o, cycloalkyl or heterocyclyl, said cycloalkyl and heterocyclyl formed being optionally substituted with 1 or 2 substituents selected from R ²;

r ²⁴、R²⁵、R⁰³、R² and m are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: Selected from the group consisting of R ² and m are as defined in formula (I);

In some embodiments of the present invention, in some embodiments, Selected from the group consisting of R ² is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxy, and C _1-6 hydroxyalkyl; m is 0,1 or 2;

In some embodiments of the present invention, in some embodiments, Selected from the group consisting of

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment (B1), (B2) thereof, wherein: x is NR ^2g or O, R ^2g is a hydrogen atom or C _1-6 alkyl; preferably, X is NH or O; in some embodiments, X is NH; in some embodiments, X is O.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment (B1), (B2) thereof, wherein: r ^2g is a hydrogen atom or a C _1-6 alkyl group; in some embodiments, R ^2g is a hydrogen atom or ethyl; preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment (B1), (B2) thereof, wherein: r ^2a and R ^2b are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxy and C _1-6 hydroxyalkyl.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment thereof (B2), wherein: r ^2e and R ^2f are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxy and C _1-6 hydroxyalkyl; in some embodiments, R ^2e and R ^2f are the same or different and are each independently a hydrogen atom or a C _1-6 alkyl group; in some embodiments, R ^2e and R ^2f are both hydrogen atoms.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment (B1), (B2) thereof, wherein: r ^2c and R ^2d are the same or different and are each independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxy and C _1-6 hydroxyalkyl, or R ^2c、R^2d together with the carbon atoms to which they are attached form a3 to 10 membered cycloalkyl or a3 to 10 membered heterocyclyl; preferably, R ^2c and R ^2d are both hydrogen atoms, or R ^2c、R^2d together with the carbon atoms to which they are attached form a3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclyl; in some embodiments, R ^2c and R ^2d are both hydrogen atoms, or R ^2c、R^2d together with the carbon atoms to which they are attached form cyclopropyl.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ^2g is a hydrogen atom or a C _1-6 alkyl group; in some embodiments, R ^2g is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: each R ² is the same or different and is each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxy, and C _1-6 hydroxyalkyl; preferably, each R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl; more preferably, each R ² is the same or different and is each independently C _1-6 alkyl; most preferred is ethyl.

In some embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt or fragment (A2), (A1), (A2), (A3) thereof, wherein: each R ⁸ is the same or different and is each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; preferably, each R ⁸ is the same or different and is each independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably halogen; most preferably F.

In some embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt or fragment (A2), (A1), (A2), (A3) thereof, wherein: each R ⁸ is the same or different and is each independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl, and n is 0 or 1; preferably, R ⁸ is halogen and n is 1.

In some embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt or fragment (a 2), (A1), (A3) thereof, wherein: each R ⁸ is the same or different and is each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclyl, 6 to 10 membered aryl and 5 to 14 membered heteroaryl, each independently and optionally substituted with a member selected from halogen, C _1-6 alkyl, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclyl, 6 to 10 membered aryl and 5 to 14 membered heteroaryl, One or more substituents of C _1-6 haloalkyl, C _1-6 alkoxy and halo C _1-6 alkoxy; Preferably, each R ⁸ is the same or different and is each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, Halogenated C _1-6 alkoxy, 6 to 10 membered aryl, and 5 to 14 membered heteroaryl; More preferably, each R ⁸ is the same or different and is each independently halogen or 6 membered heteroaryl; most preferably, R ⁸ is a fluorine atom or a pyridinyl group.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment (a 1), (a 2) thereof, wherein: r ^j、R^k and the carbon atom to which it is attached form a 3-to 6-membered cycloalkyl or 3-to 6-membered heterocyclyl, each of which is independently optionally substituted with 1,2 or 3 substituents selected from R ⁰³; in some embodiments, R ^j、R^k and the carbon atom to which it is attached form a 3-to 6-membered cycloalkyl or 3-to 6-membered heterocyclyl, each of which 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl independently is optionally substituted with 1,2, or 3 substituents selected from oxo, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; in some embodiments, R ^j、R^k together with the carbon atom to which it is attached form cyclopropyl.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ³ is selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; preferably, R ³ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ⁴ is a hydrogen atom or a C _1-6 alkyl group; preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ⁵ is selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group, and a 3 to 6 membered cycloalkyl group; preferably a hydrogen atom or a C _1-6 alkyl group; more preferably a C _1-6 alkyl group; most preferably methyl.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ⁶ is selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; preferably, R ⁶ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ³ is a hydrogen atom, and/or R ⁶ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ⁴ is a hydrogen atom, and R ⁵ is C _1-6 alkyl; preferably, R ⁴ is a hydrogen atom and R ⁵ is methyl.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: r ⁷ is a hydrogen atom or a C _1-6 alkyl group; preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: each of R ²⁰、R²¹、R²²、R²⁴、R²⁵、R²⁶、R^a、R^b and R ^c is the same or different and is each independently a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: each of R ²³、R²⁷ and R ^d is the same or different and is each independently a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt or fragment (a 2), (A1) thereof, wherein: n is 0 or 1; preferably 1.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2,3 or 4; preferably 0, 1 or 2; more preferably 0.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt or fragment (A1), (a 2), (A1) thereof, wherein s is 0 or 1, preferably 1.

In some embodiments of the present disclosure, the compound of formula (I), (II) or (IV) or a pharmaceutically acceptable salt or fragment (A2) thereof, wherein: q is 0 or 1, preferably 0.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or fragment (B1), (B2) thereof, wherein: p is 0, 1 or 2; in some embodiments, p is 1.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: u is 1.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein: each R ⁰³ is the same or different and is each independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein G is N; ring B is a 3 to 12 membered cycloalkyl or 3 to 12 membered heterocyclyl; each R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl; r ³ is a hydrogen atom; r ⁴ is a hydrogen atom; r ⁵ is C _1-6 alkyl; r ⁶ is a hydrogen atom; r ⁷ is a hydrogen atom; ring A isEach R ⁸ is the same or different and is each independently halogen or 6 membered heteroaryl; n is 1; and m is 0,1 or 2.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein G is N; ring B is selected fromEach R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl; r ³ is a hydrogen atom; r ⁴ is a hydrogen atom; r ⁵ is C _1-6 alkyl; r ⁶ is a hydrogen atom; r ⁷ is a hydrogen atom; ring A is Each R ⁸ is the same or different and is each independently halogen or 6 membered heteroaryl; n is 1; and m is 0,1 or 2.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3 to 12 membered cycloalkyl or a 3 to 12 membered heterocyclyl; each R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl; r ³ is a hydrogen atom; r ⁴ is a hydrogen atom; r ⁵ is C _1-6 alkyl; r ⁶ is a hydrogen atom; r ⁷ is a hydrogen atom; q ¹ is O, Q ² is O; r ⁸ is halogen; n is 1; s is 1; and m is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein; ring B is selected fromEach R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl; r ³ is a hydrogen atom; r ⁴ is a hydrogen atom; r ⁵ is C _1-6 alkyl; r ⁶ is a hydrogen atom; r ⁷ is a hydrogen atom; q ¹ is O and Q ² is O; r ⁸ is halogen; n is 1; s is 1; and m is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein; ring B is a 4 to 7 membered heterocyclyl; each R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl; r ³ is a hydrogen atom; r ⁴ is a hydrogen atom; r ⁵ is C _1-6 alkyl; r ⁶ is a hydrogen atom; r ⁷ is a hydrogen atom; r ^8b is a hydrogen atom; q is 0; and m is 0,1 or 2.

In some embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein; ring B is selected fromEach R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl; r ³ is a hydrogen atom; r ⁴ is a hydrogen atom; r ⁵ is C _1-6 alkyl; r ⁶ is a hydrogen atom; r ⁷ is a hydrogen atom; r ^8b is a hydrogen atom; q is 0; and m is 0, 1 or 2.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (IA):

Wherein R ^w is an amino protecting group, preferably PMB;

Ring a, ring B, G, R ²、R³、R⁵ to R ⁸, n and m are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA):

Wherein R ^w is an amino protecting group, preferably PMB;

The rings B, Q ¹、Q²、R²、R³、R⁵ to R ⁸, s, n and m are as defined in the general formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (IIIA):

Wherein R ^w is an amino protecting group, preferably PMB;

The rings B, R ²、R³、R⁵ to R ⁸、R⁰, n and m are as defined in the general formula (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (IVA):

Wherein R ^w is an amino protecting group, preferably PMB;

The rings B, R ²、R³、R⁵ to R ⁷、R^8a、R^8b, q and m are as defined in the general formula (IV).

Table B typical intermediate compounds of the present disclosure or salts thereof include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection reaction of a compound represented by the general formula (IA) or a salt thereof to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

Another aspect of the present disclosure relates to a method for preparing a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, which comprises:

Deprotection of a compound represented by the general formula (IIA) or a salt thereof to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

Another aspect of the present disclosure relates to a method for preparing a compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, which comprises:

Deprotection of a compound of formula (IIIA) or a salt thereof to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

Another aspect of the present disclosure relates to a method for preparing a compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, which comprises:

Deprotection reaction of a compound represented by the general formula (IVA) or a salt thereof to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III) or (IV) of the present disclosure and table a or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure further relates to the use of a compound of formula (I), (II), (III) or (IV) as well as a compound shown in table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TYK2 activity.

The disclosure further relates to the use of a compound of formula (I), (II), (III) or (IV) as well as a compound shown in table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a TYK2 inhibitor.

The disclosure further relates to the use of a compound of formula (I), (II), (III) or (IV) as well as table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a disease or disorder mediated or dependent by TYK 2.

The disclosure further relates to the use of a compound of formula (I), (II), (III) or (IV) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a proliferative disease, a metabolic disease, an allergic disease, an inflammatory disease and an autoimmune disease; preferably, the method comprises the steps of, the inflammatory or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis, psoriatic arthritis, intestinal tract disease, crohn's disease, sjogren's syndrome, systemic disease scleroderma, ulcerative colitis, graves ' disease, discoid lupus erythematosus, adult stell's disease, juvenile idiopathic arthritis, gout, gouty arthritis, sepsis, septic shock, shigella disease, pancreatitis, glomerulonephritis, idiopathic nephritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, vitiligo, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, lung hemorrhagic nephritis syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-related small vasculitis, pemphigus, kawasaki's disease, chronic inflammatory demyelinating polyneuropathy, baryositis, polymyositis, autoimmune disease, autoimmune disease; more preferably, the inflammatory or autoimmune disease is selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease; the metabolic disease is preferably diabetes; the proliferative disease is preferably cancer; the cancer is preferably selected from breast cancer, cervical cancer, colorectal cancer, lung cancer, gastric cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.

The present disclosure also relates to a method of treating and/or preventing a disease or condition mediated or dependent by TYK2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of inhibiting TYK2 activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing a proliferative disease, a metabolic disease, an allergic disease, an inflammatory disease, and an autoimmune disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the inflammatory or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis, psoriatic arthritis, intestinal tract disease (INTESTINAL BOWEL DISEASE), crohn's disease, sjogren's syndrome, systemic disease scleroderma, ulcerative colitis, graves ' disease, discoid lupus erythematosus, adult stell disease, juvenile idiopathic arthritis, gout, gouty arthritis, sepsis, septic shock, shigellosis, pancreatitis, glomerulonephritis, idiopathic nephritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, vitiligo, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, lung hemorrhagic syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-related small vasculitis, pemphigus, kawasaki disease, chronic inflammatory demyelinating disease, polymyositis, polymyelinating, autoimmune disease, autoimmune disease; more preferably, the inflammatory or autoimmune disease is selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease; the metabolic disease is preferably diabetes; the proliferative disease is preferably cancer; the cancer is preferably selected from breast cancer, cervical cancer, colorectal cancer, lung cancer, gastric cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.

The present disclosure further relates to a compound of the above general formula (I), (II), (III) or (IV) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound of the above general formula (I), (II), (III) or (IV) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a TYK2 inhibitor.

The present disclosure further relates to a compound of the above general formula (I), (II), (III) or (IV) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting TYK2 activity.

The present disclosure further relates to a compound of the general formula (I), (II), (III) or (IV) or table a above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder mediated or dependent by TYK 2.

The present disclosure further relates to compounds of the above general formula (I), (II), (III) or (IV) or table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TYK2 activity.

The present disclosure further relates to compounds of the general formula (I), (II), (III) or (IV) or table a above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of diseases or disorders mediated by TYK2 or dependent thereon.

The present disclosure further relates to a compound represented by the above general formula (I), (II), (III) or (IV) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a proliferative disease, a metabolic disease, an allergic disease, an inflammatory disease, and an autoimmune disease; preferably, the method comprises the steps of, the inflammatory or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis, psoriatic arthritis, intestinal tract disease, crohn's disease, sjogren's syndrome, systemic disease scleroderma, ulcerative colitis, graves ' disease, discoid lupus erythematosus, adult stell's disease, juvenile idiopathic arthritis, gout, gouty arthritis, sepsis, septic shock, shigella disease, pancreatitis, glomerulonephritis, idiopathic nephritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, vitiligo, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, lung hemorrhagic nephritis syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-related small vasculitis, pemphigus, kawasaki's disease, chronic inflammatory demyelinating polyneuropathy, baryositis, polymyositis, autoimmune disease, autoimmune disease; more preferably, the inflammatory or autoimmune disease is selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease; the metabolic disease is preferably diabetes; the proliferative disease is preferably cancer; the cancer is preferably selected from breast cancer, cervical cancer, colorectal cancer, lung cancer, gastric cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.

Preferably, the TYK2 mediated or dependent disease or disorder described in the present disclosure is a proliferative disease, a metabolic disease, an allergic disease, an inflammatory disease or an autoimmune disease; preferably, the method comprises the steps of, the inflammatory or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis, psoriatic arthritis, intestinal tract disease, crohn's disease, sjogren's syndrome, systemic disease scleroderma, ulcerative colitis, graves ' disease, discoid lupus erythematosus, adult stell's disease, juvenile idiopathic arthritis, gout, gouty arthritis, sepsis, septic shock, shigella disease, pancreatitis, glomerulonephritis, idiopathic nephritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, vitiligo, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, lung hemorrhagic nephritis syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-related small vasculitis, pemphigus, kawasaki's disease, chronic inflammatory demyelinating polyneuropathy, baryositis, polymyositis, autoimmune disease, autoimmune disease; more preferably, the inflammatory or autoimmune disease is selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease; the metabolic disease is preferably diabetes; the proliferative disease is preferably cancer; the cancer is preferably selected from breast cancer, cervical cancer, colorectal cancer, lung cancer, gastric cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.

The active compounds may be formulated in a form suitable for administration by any suitable route, preferably in unit dosage form, or in a form whereby the patient may self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation.

As a general guideline, suitable unit doses may be from 0.1 to 1000mg.

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

In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.

In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt or isotopic substitution thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions comprise 0.1-99.9% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substitutions thereof. In certain embodiments, the pharmaceutical compositions comprise 0.5% to 99.5% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substituents thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substituents thereof. In certain embodiments, the pharmaceutical compositions comprise 2% to 98% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substitutions thereof.

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

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

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

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus injection. Or preferably the solution and microemulsion are administered in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the DELTEC CADD-PLUS. TM.5400 type.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

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

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group 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., a C _1-20 alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., a C _1-10 alkyl group), preferably an alkyl group having 1 to 6 carbon atoms (i.e., a C _1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, 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., a C _1-20 alkylene group). The alkylene group is preferably an alkylene group having 1 to 10 carbon atoms (i.e., a C _1-10 alkylene group), preferably an alkylene group having 1 to 8 carbon atoms (i.e., a C _1-8 alkylene group), more preferably an alkylene group having 2 to 7 carbon atoms (i.e., a C _2-7 alkylene group) or an alkylene group having 1,2 or 3 carbon atoms (i.e., a C _1-6 alkylene group). 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 may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is defined as 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 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., a C _2-6 alkenyl group). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, 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.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is defined as above having 2 to 12 (e.g., 2, 3, 4, 5, 6,7, 8, 9, 10, 11, or 12) carbon atoms (i.e., a C _2-12 alkynyl group). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, 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.

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

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, full-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system 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 is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8 membered cycloalkyl group), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a4 to 7 membered cycloalkyl group), or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5 or 6 membered cycloalkyl group); cycloalkyl groups having 5 or 6 ring atoms are most preferred.

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

The polycyclic cycloalkyl group includes: spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system having one or more carbon atoms (referred to as spiro atoms) shared between the rings, which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., to form a nitroxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-S-), provided that at least one full carbocyclic ring is contained and the point of attachment is on the full carbocyclic 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 spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spirocycloalkyl group). The spirocycloalkyl group includes a mono-spirocycloalkyl group and a multi-spirocycloalkyl group (e.g., a double spirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a double spirocycloalkyl 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/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 single spirocycloalkyl group. Non-limiting examples include:

The connection point can be at any position;

Etc.

The term "fused ring alkyl" refers to a polycyclic ring system having two adjacent carbon atoms shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, and 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 fused ring alkyl groups). The condensed ring alkyl group is preferably a condensed ring alkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered condensed ring alkyl group), more preferably a condensed ring alkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered condensed ring alkyl group). The condensed ring alkyl group includes a bicyclic condensed ring alkyl group and a polycyclic condensed ring alkyl group (e.g., a tricyclic condensed ring alkyl group, a tetracyclic condensed ring alkyl group, etc.), preferably a bicyclic condensed ring alkyl group or a tricyclic condensed ring alkyl 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, or 7-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples include: The connection point can be at any position; Etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system having two carbon atoms in common between the rings that are not directly attached, which may contain one or more double bonds within the ring, and which has from 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., a 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10 membered bridged cycloalkyl group). The bridged cycloalkyl group includes a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples include:

The connection point can be at any position.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1, 2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., forming a nitroxide; the sulfur may optionally be oxo, i.e., forming a sulfoxide or sulfone, but excluding-O-, -O-S-, or-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) within the ring. The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a3 to 12 membered heterocyclic group); further preferred are heterocyclyl groups having 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl groups); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a3 to 6 membered heterocyclic group), a heterocyclic group having 4 to 7 ring atoms (i.e., a 4 to 7 membered heterocyclic group), or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heterocyclic group); most preferred are heterocyclyl groups having 5 or 6 ring atoms.

Non-limiting examples of such monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The polycyclic heterocyclic group includes spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.

"Nitrogen-containing heterocyclyl" means a heterocyclyl having at least one (e.g., 1, 2, 3, or 4) nitrogen atom within the ring, the heterocyclyl being as defined above. Preferably a 3 to 10 membered nitrogen containing heterocyclic group, more preferably a 4 to 7 membered nitrogen containing heterocyclic group, most preferably a 5 or 6 membered nitrogen containing heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system having one or more double bonds shared between the rings, which may 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 (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-) with the proviso that at least one monocyclic heterocyclic ring is contained and the point of attachment is on the monocyclic heterocyclic 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 spiroheterocyclic groups). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spiroheterocyclyl group), more preferably a spiroheterocyclyl group having 7 to 11 ring atoms (i.e., a 7 to 11 membered spiroheterocyclyl group). The spiroheterocyclyl group includes a mono-spiroheterocyclyl group and a multi-spiroheterocyclyl group (e.g., a double-spiroheterocyclyl group, etc.), preferably a mono-or double-spiroheterocyclyl group, more preferably a 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-membered mono-spiroheterocyclyl group. Non-limiting examples include:

Etc.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system having two adjacent atoms shared between the rings, which may 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 within the ring (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-), which is a monocyclic heterocyclic group fused to one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused to one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on a monocyclic heterocyclic group 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 heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes a bicyclic and polycyclic fused heterocyclic group (e.g., a tricyclic fused heterocyclic group, a tetracyclic fused heterocyclic group, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic 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 bicyclic fused heterocyclic group. Non-limiting examples include:

Etc.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system having two atoms not directly connected between the rings, which may 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 within the ring (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-or-S-), 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 heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10 membered bridged heterocyclic group). The number of constituent rings may be classified into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (e.g., a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), with a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group being preferred. Non-limiting examples include:

Etc.

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

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having from 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) having a conjugated pi electron system. The aryl group is preferably an aryl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered aryl group), more preferably an aryl group having 6 to 10 ring atoms (i.e., a 6 to 10 membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of such polycyclic aryl groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes a phenyl group fused to one or more of a heterocyclic group or a cycloalkyl group, or a naphthyl group fused to one or more of a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

Etc.

Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated pi electron system, the ring of which contains at least one (e.g., 1, 2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-), 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 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).

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridones (e.g.)Etc.), pyrazinyl, pyridazinyl, etc.

Non-limiting examples of such polycyclic heteroaryl groups include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more of a cycloalkyl or heterocyclic group, where the point of attachment is on the monocyclic heteroaryl ring, and in such a case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

Etc.

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

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

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

The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl, alkyl are as defined above.

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

The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein alkyl, aryl are as defined above.

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

The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein alkyl, heteroaryl are as defined above.

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "amino" refers to-NH ₂.

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂.

The term "oxo" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

TBS means t-butyldimethylsilyl.

The term "amide" refers to-CONH ₂.

The term "alkylene amino" refers to an-alkylene-amino group, wherein alkylene and amino are as defined above.

The term "alkylene amide" refers to an-alkylene-amide group, wherein alkylene and amide groups are as defined above.

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyloxycarbonyl (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.

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement of atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr (b)Or at the same time containAndTwo configurations. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any proportions. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. Examples of lactam-lactam balances are shown below:

As reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

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

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as ² H (deuterium, D), ³ H (tritium ,T)、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²p、³³p、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁵I、¹²⁹I and ¹³¹ I, respectively, and the like, with deuterium being preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

When a position is specifically designated as deuterium D, that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%), i.e. at least 15% deuterium incorporation. The natural abundance of the compounds in the examples may be at least 1000 times greater than the abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times greater than the abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times greater than the abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times greater than the abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times greater than the abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times greater than the abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times greater than the abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times greater than the abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times greater than the abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times greater than the abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times greater than the abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times greater than the abundance of deuterium (i.e., at least 6600 times greater than the abundance of deuterium (i.99% of deuterium incorporation), or at least 6600 times greater than the abundance of deuterium (i.5% of deuterium incorporation).

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the event or circumstance includes instances where it occurs or is not. For example, "C _1-6 alkyl optionally substituted with halogen or cyano" includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen or cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms, preferably 1,2 or 3, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., alkenes).

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. May be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.

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

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

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

Scheme one

The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

Deprotection reaction of a compound represented by the general formula (IA) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

Scheme II

The preparation method of the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof comprises the following steps:

Deprotection reaction of a compound represented by the general formula (IIA) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

Scheme III

The preparation method of the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof comprises the following steps:

deprotection reaction of a compound represented by the general formula (IIIA) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

Scheme IV

The preparation method of the compound shown in the general formula (IV) or the pharmaceutically acceptable salt thereof comprises the following steps:

deprotection reaction of a compound represented by the general formula (IVA) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

The reagent for providing acidic conditions in the above schemes includes organic acids including but not limited to hydrochloric acid, sulfuric acid, nitric acid, hydrogen chloride, 1, 4-dioxane, hydrochloric acid, 1, 4-dioxane, etc., and inorganic acids including but not limited to acetic acid, trifluoroacetic acid, tartaric acid, sulfonic acid, etc.; preferably trifluoroacetic acid.

The reaction of the above steps is preferably carried out in solvents including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

Detailed Description

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

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 ^-6 (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD) and Tetramethylsilane (TMS) as internal standard.

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS (manufacturer: agilent, MS model: 6110/6120 Quadrupole MS).

Waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

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

High Performance Liquid Chromatography (HPLC) analysis used AGILENT HPLC DAD, AGILENT HPLC VWD, and WATERS HPLC E2695-2489 high performance liquid chromatographs.

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

The high performance liquid phase was prepared by using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

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

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

The average inhibition rate of kinase and IC ₅₀ were measured by NovoStar microplate reader (BMG, germany).

The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & Co.KG, acros Organics, ALDRICH CHEMICAL Company, shaoshan chemical technology (Accela ChemBio Inc), dary chemistry, shanghai Leaching, shanghai Pichia, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses Parr 3916EKX type hydrogenometer and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: the volume ratio of the petroleum ether to the ethyl acetate is adjusted according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

(5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) (isoxazolidin-2-yl) methanone 1

5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- ((4-methoxybenzyl) (methyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester 1c

Ethyl 5-chloro-7- ((4-methoxybenzyl) (methyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 1a (200 mg, 533.58. Mu. Mol, prepared as disclosed in patent application "WO2020055636A1" at page 14, preparation 3), 7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-5-amine 1b (99.3 mg, 586.9. Mu. Mol, prepared as disclosed in patent application "US 2014371217A 1" at page 34, int-52) was dissolved in 1, 4-dioxane (5 mL), palladium acetate (12 mg, 53.4. Mu. Mol), 2 '-bis (diphenylphosphine) -1,1' -binaphthyl (67 mg, 106.7. Mu. Mol), cesium carbonate (mg, 801. Mu. Mol), 115℃were reacted for 16 hours, the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was eluted with silica gel column chromatography (73 mg ) to obtain the title compound (1 c) as a purified by chromatography.

MS m/z(ESI):508.2[M+1]。

Second step

5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- ((4-methoxybenzyl) (methyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 1d

Compound 1c (100 mg, 197. Mu. Mol) was dissolved in methanol (2 mL), water (2 mL) and tetrahydrofuran (2 mL), lithium hydroxide monohydrate (82.8 mg,1.97 mmol) was added, the reaction was carried out at 60℃for 14 hours, the reaction mixture was concentrated under reduced pressure, diluted with water was added, pH was adjusted to 6 with 1M hydrochloric acid, dichloromethane was extracted (10 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and after removal of the drying agent by filtration, concentrated under reduced pressure to give the crude title compound 1d (90 mg), which was used in the next reaction without purification.

MS m/z(ESI):478.1[M-1]。

Third step

5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- ((4-methoxybenzyl) (methyl) amino) pyrazolo [1,5-a ] pyrimidin-3-yl) (isoxazolidin-2-yl) methanone 1e

Crude compound 1d (52 mg, 108.4. Mu. Mol), isoxazolidine hydrochloride (18 mg, 164. Mu. Mol, TCI) was dissolved in N, N-dimethylacetamide (2 mL), N, N-diisopropylethylamine (43 mg, 332. Mu. Mol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (62 mg, 163. Mu. Mol) was added, the reaction mixture was stirred for 5 hours, water was added, extracted with dichloromethane (10 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give crude title compound 1e (58 mg), which was used in the next reaction without purification.

MS m/z(ESI):535.2[M+1]。

Fourth step

The crude compound 1e (58 mg, 108.5. Mu. Mol) was dissolved in dichloromethane (2 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 dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35% -45%, flow rate: 30 mL/min) to give the title compound 1 (44 mg, yield: 97%).

MS m/z(ESI):415.2[M+1]。

¹H NMR(500MHz,CDCl₃):δ8.44(s,1H),7.88(s,1H),6.39(s,1H),6.28(s,1H),5.57(s,1H),5.32(s,1H),4.32(s,4H),4.15-3.90(m,4H),3.10(s,3H),2.43-2.28(m,2H).

Example 2

(5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) (5, 6-diazaspiro [2.4] heptan-5-yl) methanone 2

First step

5, 6-Diazaspiro [2.4] heptane bis (2, 2-trifluoroacetate salt) 2b

Di-tert-butyl 5, 6-diazaspiro [2.4] heptane-5, 6-dicarboxylate 2a (60 mg, 201. Mu. Mol, prepared by the method disclosed in the literature "Journal of MEDICINAL CHEMISTRY,2018, vol.61, #3, p.865-880") was dissolved in methylene chloride (2 mL), trifluoroacetic acid (3 mL) was added, the reaction was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure to give the crude title compound 2b (65 mg), the product was directly used in the next reaction without purification.

MS m/z(ESI):99[M+1]。

Second step (5- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- ((4-methoxybenzyl) (methyl) amino) pyrazolo [1,5-a ] pyrimidin-3-yl) (5, 6-diazaspiro [2.4] heptan-5-yl) methanone 2c

Crude compound 1d (96 mg, 200.2. Mu. Mol), crude compound 2b (65 mg, 201. Mu. Mol) was dissolved in N, N-dimethylacetamide (2 mL), N, N-diisopropylethylamine (129.4 mg,1 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (152.2 mg, 400.4. Mu. Mol) was added, the reaction mixture was stirred for 2 hours, water was added, extracted with dichloromethane (10 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate after removal of the drying agent by filtration was concentrated under reduced pressure to give crude title compound 2c (112 mg), which was used directly for the next reaction without purification.

MS m/z(ESI):560.2[M+1]。

Third step (5- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) (5, 6-diazaspiro [2.4] heptan-5-yl) methanone 2

The crude compound 2c (60 mg, 107.2. Mu. Mol) was dissolved in dichloromethane (2 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 dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound 2 (25 mg, yield: 53%).

MS m/z(ESI):440.2[M+1]。

¹H NMR(500MHz,CDCl₃):δ8.33(s,1H),7.74(d,1H),7.05(s,1H),6.37(dd,1H),6.30-6.24(m,1H),5.43(s,1H),4.37-4.29(m,4H),3.77(s,2H),3.07(d,3H),2.95(s,2H),1.34(s,1H),0.82(s,2H),0.72(t,2H).

Example 3

(5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) (pyrazolin-1-yl) methanone 3

Using the synthetic routes from the third to fourth steps of example 1, substituting the starting compound isoxazolidine hydrochloride from the third step with pyrazoline dihydrochloride (Shanghai Bifide) gives the title compound 3 (5 mg, yield: 32.2%). MS m/z (ESI) 414.2[ M+1].

¹H NMR(500MHz,CDCl₃):δ8.32(s,1H),7.73(d,1H),7.33(s,1H),7.01(s,1H),6.36(dd,1H),6.24(d,1H),5.42(s,1H),4.33(q,3H),3.83(t,2H),3.09(dd,4H),2.17(p,2H),1.28(d,2H).

Example 4

(5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) (5-oxa-6-azaspiro [2.4] heptan-6-yl) methanone 4

First step

5-Oxa-6-azaspiro [2.4] heptane-6-carboxylic acid tert-butyl ester 4c

Tert-butyl N-hydroxycarbamate 4a (470 mg,3.53mmol, shanghai Biao) was dissolved in N, N-dimethylformamide (10 mL), sodium hydrogen (296.5 mg,7.4mmol,60% purity) was added at 0deg.C, cyclopropane-1, 1-diylbis (methylene) dimethyl sulfonate 4b (450 mg,3.17mmol, prepared as described in literature "Organic Letters,2022, vol.24, #23, p.4176-4181") was added after stirring at temperature for 1 hour, the reaction was resumed for 16 hours, ice water quench was added to the reaction solution, filtration was performed, the filter cake was washed with water, the filter cake was collected, and the crude title compound 4c (100 mg) was obtained after drying, without purification, and was directly used in the next reaction.

MS m/z(ESI):144.0[M-55]。

Second step (5- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) (5-oxa-6-azaspiro [2.4] heptan-6-yl) methanone 4

Using the synthetic route of example 2, the first starting compound 2a was replaced with compound 4c to afford title compound 4 (8 mg, yield: 10.1%).

MS m/z(ESI):441.2[M+1]。

¹H NMR(500MHz,CDCl₃):δ8.46(s,1H),7.88(dd,1H),7.18(s,1H),6.37(dd,1H),6.23(d,1H),5.58(s,1H),4.32(s,4H),3.95(d,4H),3.09(d,3H),0.83(d,2H),0.80(d,2H).

Example 5

3- ((7- (Methylamino) -3- (pyrazolidine-1-carbonyl) pyrazolo [1,5-a ] pyrimidin-5-yl) amino) -2H- [1,2' -bipyridin ] -2-one 5

First step

7- ((4-Methoxybenzyl) (methyl) amino) -5- ((2-oxo-2H- [1,2' -bipyridyl ] -3-yl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 5b

Using the first and second steps of the synthetic route in example 1, the first step starting compound 1b was replaced with 3-amino-2H- [1,2' -bipyridin ] -2-one 5a (prepared using the procedure disclosed in literature "ACS MEDICINAL CHEMISTRY LETTERS,2019, vol.10, #3, p.383-388") to give crude title compound 5b (200 mg).

MS m/z(ESI):498.2[M+1]。

Second step

3- ((7- ((4-Methoxybenzyl) (methyl) amino) -3- (pyrazolidine-1-carbonyl) pyrazolo [1,5-a ] pyrimidin-5-yl) amino) -2H- [1,2' -bipyridin ] -2-one 5c

Crude compound 5b (255 mg, 508.5. Mu. Mol) was dissolved in N, N-dimethylacetamide (3 mL), N, N-diisopropylethylamine (328.6 mg,2.5 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (309.3 mg, 813.6. Mu. Mol) and stirred for 14 hours, water was added to the reaction solution, extracted with dichloromethane (10 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate after filtration to remove the drying agent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 5c (100 mg, yield: 35.6%).

MS m/z(ESI):552.2[M+1]。

Third step

The crude compound 5c (100 mg, 181.3. Mu. Mol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35% -45%, flow rate: 30 mL/min) to give the title compound 5 (10 mg, yield: 12.7%).

MS m/z(ESI):432.2[M+1]。

¹H NMR(500MHz,CDCl₃):δ8.80(dd,1H),8.67-8.61(m,1H),8.45(s,1H),8.10(s,1H),7.98-7.87(m,2H),7.53(dd,1H),7.42-7.36(m,1H),6.49(t,1H),6.21(d,1H),5.47(s,1H),3.86(t,2H),3.16-3.06(m,4H),2.15(td,2H),1.28(s,2H).

Example 6

(2-Ethylpyrazolid-1-yl) (5- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) methanone 6

First step

(5- ((7-Fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- ((4-methoxybenzyl) (methyl) amino) pyrazolo [1,5-a ] pyrimidin-3-yl) (pyrazolidin-1-yl) methanone 6a

Crude compound 1d (300 mg, 625.7. Mu. Mol), pyrazoline dihydrochloride (136 mg, 937.7. Mu. Mol) was dissolved in N, N-dimethylacetamide (10 mL), N, N-diisopropylethylamine (243 mg,1.88 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (317 mg, 938.9. Mu. Mol) was added, stirred for 2 hours, water was added to the reaction mixture to precipitate a solid, filtered, and the cake was washed with water, dried to give crude title compound 6a (235 mg), which was used in the next reaction without purification.

MS m/z(ESI):534.2[M+1]。

Second step (2-Ethylpyrazol-1-yl) (5- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- ((4-methoxybenzyl) (methyl) amino) pyrazolo [1,5-a ] pyrimidin-3-yl) methanone 6b

The crude title compound 6a (55 mg, 103.08. Mu. Mol) was dissolved in N, N-dimethylacetamide (2 mL) under ice bath, sodium hydride (5 mg, 125.01. Mu. Mol,60% purity) was added, ethyl iodide (25 mg, 160.3. Mu. Mol) was added after reaction at a maintained temperature for 30 minutes, room temperature was restored for 2 hours, water was added to the reaction solution, extraction with methylene chloride (10 mL. Times.2) was performed, the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude title compound 6b (35 mg), which was directly used for the next reaction without purification.

MS m/z(ESI):562.2[M+1]。

Third step (2-Ethylpyrazol-1-yl) (5- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) -7- (methylamino) pyrazolo [1,5-a ] pyrimidin-3-yl) methanone 6

The crude compound 6b (35 mg, 62.3. Mu. Mol) was dissolved in dichloromethane (5 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 dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound 6 (15 mg, yield: 54.5%).

MS m/z(ESI):442.2[M+1]。

¹H NMR(500MHz,CDCl₃):δ8.29(s,1H),δ7.26-7.24(m,1H),6.73-6.69(m,1H),6.61-6.59(m,1H),4.32-4.22(m,2H),4.08-4.02(m,2H),3.82(s,3H),3.18-3.12(m,2H),3.01-2.96(m,2H),2.26-2.20(m,2H),2.07-2.03(m,2H),1.33-1.26(m,3H).

Biological evaluation

Test example 1: TYK2 JH2 in vitro enzyme binding assay

The present experiment uses fluorescence resonance energy transfer (TR-FRET) to test compounds for inhibition of TYK2 JH2 and JAK1 JH2 pseudokinases. In the experiment, TYK2 JH2 or JAK1 JH2 pseudokinase can be combined with a fluorescence-labeled Tracer and a Tb antibody simultaneously, the Tb antibody is taken as a fluorescence donor to generate 495nm wavelength fluorescence under the action of excitation light with a certain wavelength, and the Tracer is taken as a fluorescence acceptor, and the fluorescence with the wavelength of 495nm can be received only under the condition of being close enough to the Tb antibody, so that 520nm wavelength fluorescence, namely fluorescence resonance energy transfer signals, can be generated. When the added compound competes with the Tracer for binding to the pseudo kinase JH2 region, the TR-FRET signal is reduced due to reduced Tracer binding, and the inhibition of binding of the compound to the pseudo kinase can be reflected by a signal ratio of 520nm/495 nm.

1. Experimental reagent and instrument

Micropipette apparatus Echo (LABCYTE Echo550,550)

Enzyme label instrument, envision2105 (PERKIN ELMER)

Constant temperature incubator CIMO, SPX-60BS-II

Thermo MATRIX multichannel pipette, thermo Fisher, 2-125. Mu.L

Centrifuge Thermo Centrifuge ST R

Pure water meter Millipore Milli-Q REFERENCE SYSTEM

Ultra-low temperature refrigerator Haier ultralow temperature freezer

Refrigerator: haier 4degree freezer; haier-20degree freezer

2. Experimental method

2.1. Preparation of 1X experiment working solution

Composition of the components	Final concentration (mM)
		HEPES pH7.5	20
MgCl₂	10
		Brij-35	0.015％
DTT	2
		BSA	50μg/mL

2.2. The experimental procedure was as follows:

2.2.1. the compound was dissolved with DMSO to a storage concentration of 10 mM.

2.2.2. Different concentration gradients of compound were prepared in compound dilution plates at 200 times the final concentration and transferred to Echo plates.

2.2.3. Compounds were transferred from the Echo plate to the 384 assay plates using an Echo instrument from 75 nL.

2.2.4. Mu.L of pseudokinase 3 times the final concentration (0.5 nM final concentration) TYK2 JH2 and JAK1 JH2 were added to 384 well plates, respectively, and centrifuged at 1000rpm for 30 seconds.

2.2.5. Mu.L of Tb antibody 3 times the final concentration (1X the final concentration) was added to 384-well plates, respectively, and centrifuged at 1000rpm for 30 seconds.

2.2.6. Mu.L of Tracer 3 times the final concentration (final concentration: TYK2 JH2 1nM, JAK1 JH2 30nM, respectively) was added to 384 well plates, and centrifuged at 1000rpm for 30 seconds.

2.2.7. Incubate for 60 minutes at room temperature, incubate overnight at 4 ℃.

The fluorescence signal ratio of 520nm/495nm was read by an envision microplate reader (Perkinelmer).

3. Data analysis

Test data processing and analysis was performed using software XLfit, written by IDBS, integrated in the Microsoft Excel environment. Firstly, respectively calculating the reaction signal average value of the high signal control well and the bottom signal control well, and then calculating the reaction inhibition rate of each compound well according to the formula of "% single well inhibition rate=100- (high signal control group average value-single well signal value)/(high signal control group average value-bottom signal control group average value)". And then the concentration and the corresponding inhibition rate data are imported into XLfit software, a Dose Response One Site model in the software is utilized, a four-parameter inhibition rate-concentration curve is adopted for fitting, and the IC ₅₀ value of the compound is calculated.

TABLE 1 IC for TYK2-JH2 and JAK1-JH2 pseudokinase binding inhibition Activity ₅₀

Compounds of formula (I)	TYK2-JH2 IC₅₀(nM)	JAK1-JH2 IC₅₀(nM)
			1	0.063	516
3	0.87	5072

Conclusion: the compound disclosed by the disclosure has obvious selective inhibition effect on TYK2-JH2 pseudokinase.

Test example 2: pSTAT3 ELISA assay of the presently disclosed Compounds on IFN alpha-induced human T lymphocytes

Cryopreserved human PBMCs were resuscitated with RPMI 1640 complete growth medium containing 10% inactivated FBS. T cells in PBMCs were sorted according to T cell sorting kit and cultured overnight. Overnight cultured T cells were seeded at 1 x 10 ⁵/well in 96-well plates. Cells were treated with serial dilutions of the compounds and incubated for 1 hour at 37℃in a &5% CO ₂ incubator. IFNα was added at a final concentration of 200ng/mL and incubated for 30 minutes at 37℃in a 5% CO ₂ incubator. The treated cells were then lysed and the level of cell phosphorylated STAT3 was measured by the Elisa kit according to the manufacturer's instructions. Inhibition data were calculated by comparing 0% inhibition with ifnα/DMSO control wells and 100% inhibition with non-stimulated control wells. A dose response curve was then generated to determine the concentration required to inhibit 50% of the cellular response (IC ₅₀), which was determined by non-linear regression analysis using GRAPHPAD PRISM.

TABLE 2 inhibitory Activity of the presently disclosed compounds against IFN-alpha_pSTAT3

Compounds of formula (I)	IC₅₀(nM)
		1	2.52

Conclusion: the compounds of the present disclosure have an inhibitory effect on TYK 2-mediated, ifnα -induced STAT3 phosphorylation in human T lymphocytes.

Test example 3: experiments on HeLa cell IFN alpha-induced inhibition of STAT1 protein phosphorylation by Compounds of the present disclosure

The inhibition of HeLa cell ifnα -induced STAT1 protein phosphorylation by the compounds of the present disclosure was examined using the method of AlphaLISA, and the specific content is as follows:

1.1 reagents and instruments

1.1.1 Reagents

1.1.2 Instruments

Instrument name	Manufacturer' s	Model information
			Automated cell counter	Countstar	IC1000
Hood	Thermo	1300AII
			Thermo Incubator	Thermo	I160
PHERASTAR HS Microplate reader	BMG LABTECH	PHERASTAR HS
			Centrifugal machine	Beckman coulter	Allegra X-12 centrifuge

1.2 Cells and culture methods

HeLa cells were purchased from American Type Culture Collection (ATCC), MEM medium (10% FBS), 37℃and 5% carbon dioxide in an incubator for 2-3 passages per week.

1.3 Preparation of Compounds

A. Test compounds were dissolved to 0.5mM with DMSO.

B. initial concentration of compound 0.5mM, 3-fold dilution, 10 concentration gradients.

C. all concentrations of compounds were diluted 50-fold with culture medium for use.

4. Experimental procedure

A. cell counts, cell densities were adjusted to 5X 10 ⁵/mL with fresh medium.

96Well Black Polystyrene Microplate, 80. Mu.L of cells per well were inoculated and incubated at 37℃for 4 hours.

C. mu.L of compound (column 1 and column 12 plus 10. Mu.L of 0.5% DMSO) was added to each well and incubated at 37℃for 1 hour.

D. 100ng/mL of IFN alpha was prepared from the culture solution, 10. Mu.L of IFN alpha was added to each well (column 1 plus 10. Mu.L of the culture solution as a control), and incubated at 37℃for 15 minutes.

E. The lysis solution was prepared according to ALPHALISA SUREFIRE ULTRA STAT p Y701 kit instructions. The cell culture supernatant was aspirated off, 50. Mu.L of lysis solution was added to each well and lysed by shaking at room temperature for 15 minutes.

F. Acceptor Mix was prepared according to ALPHALISA SUREFIRE ULTRA STAT p Y701 kit instructions. In 96-well low volume WHITE PLATE. Mu. L of Acceptor Mix was added per well.

G. transfer 10. Mu.L of cell lysate to 96-well low volume WHITE PLATE, centrifuge, and incubate at room temperature for 1 hour.

H. the Donor Mix was prepared according to ALPHALISA SUREFIRE ULTRA STAT p Y701 kit instructions. In the dark, 5. Mu.L of Donor Mix was added to each well and incubated overnight at room temperature.

I. read plate detection was performed with PHERASTAR HS Microplate reader.

Graphpad software plots, calculating IC ₅₀ values for compounds of the present disclosure.

TABLE 3 inhibitory Activity of the compounds of the present disclosure against HeLa cell IFNα -induced phosphorylation of STAT1 protein

Compounds of formula (I)	IC₅₀(nM)
		1	9.8

Conclusion: the compound disclosed by the disclosure has a better inhibition effect on the phosphorylation of STAT1 protein induced by HeLa cell IFN alpha.

Test example 4: experiments in which compounds of the present disclosure inhibit ifnα -induced production of IP10 by human PMBC

Fresh PBMC cells were plated at 150 μl per well into 96-well round bottom plates, 25 μl of medium containing compounds at different concentration gradients was added per well, and incubated for 30min in a 37 degree incubator; interferon- α was added at a final concentration of 20ng/ml and incubated in a 37℃incubator for 24 hours. The supernatant was collected 24 hours. ELISA was performed to detect IP10 in the supernatant using the human IP-10/CXCL10 ELISA kit from Xinbo organisms.

And drawing a standard curve according to the standard substance, and obtaining a corresponding calculation formula, wherein Y=aX+b, and R squared is more than 0.99. Wherein Y represents OD450 value and X represents IP10 concentration. The corresponding IP10 concentrations for each OD450 value were calculated. The final concentration was 100X (pg/ml). IFN-a stimulated + DMSO treated wells were used as positive control wells and IFN-a unstimulated + DMSO treated wells were used as negative control wells. The inhibition ratio is (positive control well-test compound)/(positive control well-negative control well) ×100%.

An inhibition curve was drawn using Graphpad software from the compound concentration points and the corresponding inhibition rates, and the compound concentration at 50% inhibition rate, i.e., IC ₅₀ value, was calculated.

TABLE 4 inhibitory Activity of the compounds of the present disclosure on IFN alpha-induced human PMBC to produce IP10

Compounds of formula (I)	IC₅₀(nM)
		1	41.7

Conclusion: the compounds of the present disclosure have an inhibitory effect on human PBMC TYK 2-mediated, ifnα -induced IP10 production.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

G is N or CR ¹;

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl and heteroaryl;

each r is the same or different and is each independently 0,1 or 2;

M is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: ring a is a 6 to 14 membered aryl or a 5 or 6 membered heteroaryl; preferably, ring A isOr pyridonyl, s is 0,1,2, 3 or 4; more preferably, ring A isMost preferably, ring A is

3. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound of formula (II):

Wherein,

s is 0,1, 2, 3 or 4; n is 0,1, 2 or 3;

The rings B, R ² to R ⁸、R²⁴、R²⁵、R²⁶、R²⁷、R⁰³, R and m are as defined in claim 1.

4. A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: ring B isX is CR ^2aR^2b、NR^2g, O and S; p is 0, 1,2, 3 or 4; r ^2a、R^2b、R^2c and R ^2d are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cyano, nitro, NR ²⁴R²⁵, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more R ⁰³; or R ^2c、R^2d together with the carbon atom to which it is attached form c=o, cycloalkyl or heterocyclyl; r ^2g is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group; r ²⁴、R²⁵ and R ⁰³ are as defined in claim 1.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: ring B is selected fromPreferably, the method comprises the steps of,Selected from the group consisting of

6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: each R ⁸ is the same or different and is each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 6 to 10 membered aryl, and 5 to 14 membered heteroaryl; preferably, each R ⁸ is the same or different and is each independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably halogen.

7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: each R ² is the same or different and is each independently selected from C _1-6 alkyl, hydroxy and C _1-6 hydroxyalkyl.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: r ³ is a hydrogen atom, and/or R ⁶ is a hydrogen atom.

9. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: r ⁴ is a hydrogen atom, and R ⁵ is C _1-6 alkyl; preferably, R ⁴ is a hydrogen atom and R ⁵ is methyl.

10. A compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

11. a compound of the general formula (IA):

Wherein R ^w is an amino protecting group, preferably PMB;

ring a, ring B, G, R ²、R³、R⁵ to R ⁸, n and m are as defined in claim 1.

12. A compound of formula (IA) or a salt thereof according to claim 11, selected from any one of the following structures:

13. a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

Wherein R ^w is an amino protecting group, preferably PMB;

R ⁴ is a hydrogen atom;

14. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of a compound of general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 for the preparation of TYK2 inhibitors.

16. Use of a compound of general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment and/or prophylaxis of diseases or conditions mediated by TYK2 or dependent.

17. Use of a compound of general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment and/or prophylaxis of proliferative diseases, metabolic diseases, allergic diseases, inflammatory diseases and autoimmune diseases; preferably, the method comprises the steps of, the inflammatory or autoimmune disease is selected from the group consisting of arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis, psoriatic arthritis, intestinal tract disease, crohn's disease, sjogren's syndrome, systemic disease scleroderma, ulcerative colitis, graves ' disease, discoid lupus erythematosus, adult stell's disease, juvenile idiopathic arthritis, gout, gouty arthritis, sepsis, septic shock, shigella disease, pancreatitis, glomerulonephritis, idiopathic nephritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, vitiligo, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, lung hemorrhagic nephritis syndrome, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-related small vasculitis, pemphigus, kawasaki's disease, chronic inflammatory demyelinating polyneuropathy, baryositis, polymyositis, autoimmune disease, autoimmune disease; more preferably, the inflammatory or autoimmune disease is selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease; the metabolic disease is preferably diabetes; the proliferative disease is preferably cancer; the cancer is preferably selected from breast cancer, cervical cancer, colorectal cancer, lung cancer, gastric cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma and myeloma.