CN115448881A

CN115448881A - Heteroaryl compound, preparation method and application thereof in medicine

Info

Publication number: CN115448881A
Application number: CN202210642850.6A
Authority: CN
Inventors: 杨方龙; 何卫明; 张羚; 贺峰; 陶维康
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: 2021-06-09
Filing date: 2022-06-08
Publication date: 2022-12-09

Abstract

The disclosure relates to heteroaryl compounds, methods of their preparation, and their use in medicine. In particular, the disclosure relates to heteroaryl compounds represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds as a therapeutic agent, especially application of the compounds as an SIK inhibitor and application of the compounds in preparation of drugs for treating and/or preventing inflammatory diseases or autoimmune diseases. Wherein each group in the general formula (I) is defined in the specification.

Description

Heteroaryl compound, preparation method and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicines, and relates to a heteroaryl compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to heteroaryl compounds represented by general formula (I), a preparation method thereof, pharmaceutical compositions containing the compounds, and uses of the compounds as SIK inhibitors in preparation of drugs for treating and/or preventing inflammatory diseases or autoimmune diseases.

Background

The Salt-inducible kinase (SIK) kinases, including SIK1, SIK2 and SIK3, belong to the AMP-dependent protein kinase (AMPK) family, and these serine/threonine kinases play a key role in the regulation of cellular energy metabolism. A plurality of extracellular signals, including hormones, driver factors and the like, can further activate signal networks such as Protein Kinase A (PKA), protein Kinase C (PKC) and calcium ion-calmodulin dependent protein kinase (CaMK) by activating corresponding G protein-coupled receptor/cAMP signal pathways, and regulate various functions such as sugar metabolism, lipid metabolism, energy metabolism, cell differentiation and the like. And the SIK kinase is located at the downstream of Protein Kinase A (PKA), which directly phosphorylates the SIK kinase, increasing its binding to 14-3-3 regulatory proteins, thereby releasing and activating SIK downstream substrates, mainly comprising two classes of transcription factors, one of which is CREB-regulated transcription activators (CRTCs) and the other of which is histone deacetylase (HDAC 4,5,7, and 9). The released CRTCs and HDACs enter the cell nucleus from cytoplasm and are combined with corresponding DNA regulatory sites to play a role in transcriptional regulation. The downstream genes mainly include Pck1, G6PC which regulate metabolism and Ptgs2, IL-10, TTP and the like which are involved in inflammatory response. In addition, HDACs are also involved in deacetylation of NF-kB proteins in inflammatory signaling pathways, thereby regulating expression of inflammatory factors regulated by NF-kB.

Recent studies have shown that SIK kinase plays a crucial role in the immune response of innate immune cells, particularly macrophages and dendritic cells. Innate immune cells have a complex and multifaceted mechanism of action in the immune response. After infection or tissue injury, macrophages can show a phenotype (M1 type) promoting inflammatory progression on one hand, and secrete a large amount of proinflammatory factors including TNFa and IL-12 to start the innate immunity and the secondary immunity system of the body, so as to achieve the purpose of eliminating microbial infection and other immunogens. On the other hand, macrophages also play a role in immune regulation, and can be classified into immunoregulation type macrophages (M2 type) to secrete inflammation inhibitory factors such as IL-10 and IL-1ra, and the like, so as to ensure the control and timely elimination of inflammatory response. The M1-type macrophages that promote inflammation are closely associated with autoimmune diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. While M2 type, which regulates the inflammatory response, can effectively inhibit the development of inflammation. In addition, IL-10 knockout mice display a phenotype associated with inflammatory bowel disease and IL-10 gene deficiency is associated with the development of inflammatory bowel disease in humans. SIK kinase can inhibit the expression of IL-10 by regulating CREB transcription factor; by modulating HDAC and NFkB pathways, expression of TNFa is promoted, biasing macrophages towards the M1 phenotype. Thus, inhibition of SIK activity promotes differentiation of innate immune cells to the M2-resistant type, decreases proinflammatory factors such as TNFa, and increases the inflammatory suppressor IL-10. Thus, promoting macrophage differentiation to an immune-tolerant type by inhibiting SIK kinase activity provides a novel therapeutic mechanism for autoimmune diseases.

There are three subtypes of SIK kinases known to date, SIK1, SIK2 and SIK3. The research result of a mouse gene knockout model finds that SIK2 and SIK3 play more important roles in promoting macrophage differentiation. SIK1 is mainly involved in salt metabolism, and SIK1 knockout mice are more sensitive to high-salt-induced blood pressure elevation. The phenotype of the SIK2 knockout mouse is basically normal, and plasma triglycerides are increased to a certain extent; the SIK3 knockout mice had smaller body weights, suggesting a correlation with early skeletal development. Although there is not enough research result at present whether the inhibition of SIK kinase by small molecule compounds is consistent with the phenotype of mouse gene knockout, the selective targeting of SIK2/SIK3 by SIK small molecule kinase inhibitors developed for autoimmune diseases, and avoiding the inhibition of SIK1 is a safer and more effective development strategy.

Patents for SIK2/SIK3 inhibitors that are currently disclosed are WO2018188785A1, WO2018193084A1, WO2019198940A1, WO2019202160A2, WO2019238424A1, WO2020083926A1, WO2020239658A1, WO2019105886A1, and WO2020239660A1.

Disclosure of Invention

The object of the present disclosure is to provide a compound represented by the general formula (I):

wherein:

W ¹ is CR ^a Or an N atom;

W ² is CR ^d Or an N atom; provided that W is ¹ And W ² Not simultaneously N atom;

x is selected from O or-NR ^b ；

R ¹ Selected from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-R ⁷ 、-S-R ⁷ 、-NR ⁸ R ⁹ 、-C(O)NR ⁸ R ⁹ or-C (O) R ¹² Wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^A Substituted;

R ^A selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkenyl group, alkynyl group, cyano group, nitro group, hydroxyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, cycloalkyloxy group, heterocyclic group, heterocyclyloxy group, oxo group, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl; wherein said alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, oxo, -C (O) R ^f1 、-NR ^g2 R ^h2 、-NHC(O)OR ^f1 、-C(O)NR ^g2 R ^h2 、-S(O) ₂ R ^J1 、-S(O) ₂ NR ^g2 R ^h2 Aryl and heteroaryl, or a pharmaceutically acceptable salt thereof;

R ^a 、R ^d and R ² The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R ^b selected from the group consisting of alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

G ¹ is CR ³ Or an N atom;

R ³ 、R ⁴ and R ⁶ The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkenyl groups, alkynyl groups, cyano groups, nitro groups, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, amino groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkenyl groups, alkynyl groups, alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, cyano groups, nitro groups, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, amino groups, oxo groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ⁵ selected from hydrogen atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxyRadical and-NR ^5a R ^5b Wherein said alkenyl, alkynyl, alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^5a and R ^5b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

R ^w is-NR ^w1 R ^w2 or-NR ^w3 -；

R ^w1 And R ^w3 The same or different and each is independently selected from the group consisting of alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^w2 selected from the group consisting of hydrogen atoms, alkenyl groups, alkynyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

when R is ^w is-NR ^w3 When the N atom is not in contact with R ⁵ Together forming a heterocyclyl group, said heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷ selected from hydrogen atomsAlkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or- (CR) ¹⁰ R ¹¹ ) _r R ^c (ii) a Wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, substituted with one or more substituents;

R ⁸ and R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, substituted with one or more substituents;

or R ⁸ And R ⁹ Together with the attached N atom form a heterocyclic group, said heterocyclic group being optionally selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclic, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, substituted with one or more substituents;

R ¹⁰ and R ¹¹ Are the same or different and are each independently selectedFrom hydrogen atoms, halogens, alkenyl groups, alkynyl groups, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, and heterocyclic groups;

R ^c is cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is each independently optionally selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, substituted with one or more substituents;

R ¹² 、R ^f and R ^f1 The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, and a heterocyclic group; wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^g1 、R ^h1 、R ^g2 and R ^h2 Identical or different and each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^g1 And R ^h1 To the N atom to which they are attached, R ^g2 And R ^h2 Together with the linking N atom, form a heterocyclic group, said heterocyclyl is optionally substituted by a group selected from halogen, cyano, nitro hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy,Haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^J and R ^J1 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

r is 1,2,3,4, 5 or 6.

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

wherein:

R ^y the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 0, 1 or 2;

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

W ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ 、R ⁶ and R ^w3 As defined in formula (I).

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

wherein: w is a group of ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ To R ⁶ 、R ^w1 And R ^w2 As defined in formula (I).

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

wherein:

l is O or S;

ring a is a 3-to 12-membered heterocyclyl;

each R is ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl;

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

W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ to R ⁶ 、R ^w 、R ^f 、R ^g1 、R ^h1 、R ^J And r is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound represented by formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof is a compound represented by formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof:

wherein:

ring a is a 3-to 12-membered heterocyclic group containing at least one nitrogen atom;

R ¹⁴ selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl and-C (O) R ^f ；

t is selected from 0, 1,2,3 or 4;

L、W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ to R ⁶ 、R ¹³ 、R ^w 、R ^f And r is as defined in formula (IV).

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

wherein:

n is 0, 1 or 2;

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

t is selected from 0, 1,2,3 or 4;

L、W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ 、R ⁶ 、R ¹³ 、R ^f 、R ^w3 and r is as defined in formula (IV).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (III), the general formula (IV-1) or the general formula (IV-2), or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V-3) or the general formula (V-4), or a pharmaceutically acceptable salt thereof:

wherein:

ring a is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom;

t is selected from 0, 1,2,3 or 4;

L、W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ to R ⁶ 、R ¹³ 、R ^f 、R ^w1 、R ^w2 And r is as defined in formula (IV).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein W is ¹ Is CR ^a (ii) a And/or, W ² Is CR ^d ；R ^a And R ^d As defined in formula (I); preferably, R ^a And R ^d Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy and 3 to 8 membered cycloalkyl; more preferably, R ^a And R ^d Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; most preferably, R ^a And R ^d Are all hydrogen atoms.

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

Selected from the group consisting of:

R ¹ 、R ² 、R ^a 、R ^b and R ^d Such as a cartoonAs defined in formula (I); preferably, the first and second liquid crystal display panels are,

is composed of

R ¹ 、R ² 、R ^a 、R ^b And R ^d As defined in formula (I).

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

R ¹ Is selected from-O-R ⁷ 、-S-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；

R ⁷ Is C _1-6 Alkyl or- (CR) ¹⁰ R ¹¹ ) _r R ^c (ii) a Wherein said C _1-6 Alkyl is optionally selected from halogen, cyano, hydroxy, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J and-S (O) ₂ NR ^g1 R ^h1 Is substituted with one or more substituents of (1);

R ⁸ and R ⁹ Are the same or different and are each independently a hydrogen atom and C _1-6 An alkyl group; wherein said C _1-6 Alkyl is optionally selected from halogen, cyano, hydroxy, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J and-S (O) ₂ NR ^g1 R ^h1 Is substituted with one or more substituents of (1);

or R ⁸ And R ⁹ Together with the attached N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical,C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, oxo, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J and-S (O) ₂ NR ^g1 R ^h1 Is substituted with one or more substituents of (1);

R ¹⁰ and R ¹¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group;

R ^c is 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl, wherein said 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl is each independently optionally selected from halogen, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, oxo, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J and-S (O) ₂ NR ^g1 R ^h1 Is substituted with one or more substituents of (1);

R ^f is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl, 3-to 8-membered cycloalkyl, and 3-to 8-membered heterocyclyl; r is ^g1 And R ^h1 Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group;

R ^J is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl and 3 to 8-membered cycloalkyl;

r is 1,2 or 3.

R ¹ Is selected from-O-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；

R ⁷ Is- (CH) ₂ ) _r R ^c ；

R ⁸ And R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; or R ⁸ And R ⁹ Together with the linking N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is ^c Is a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is 1,2 or 3.

R ¹ Is selected from-O-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；

R ⁷ Is- (CH) ₂ ) _r R ^c ；

R ^c Is morpholinyl;

R ⁸ and R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; or R ⁸ And R ⁹ Together with the linking N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is 1,2 or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ¹ Is selected from-O-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；

R ⁷ Is- (CH) ₂ ) _r R ^c ；

R ^c Is morpholinyl or piperazinyl, wherein said morpholinyl and piperazinyl are each independently optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy;

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein R is ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ² Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein X is O or-NR ^b ；R ^b As defined in formula (I); preferably, R ^b Is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl and 3 to 8-membered cycloalkyl; more preferably, R ^b Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl; most preferably, R ^b Is C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein X is-NR ^b ；R ^b Is C _1-6 Alkyl, preferably methyl.

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

Selected from:

R ¹ is selected from-O-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；

R ⁷ Is- (CH) ₂ ) _r R ^c ；

R ⁸ And R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; or R ⁸ And R ⁹ Together with the linking N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is ^c Is a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally selected from halogen, C _1-6 Alkyl, and C _1-6 Substituted with one or more substituents of alkoxy; r is 1,2 or 3; preferably, R ^c Is morpholinyl; r ² 、R ^a 、R ^b And R ^d As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), or formula (V-4), or a pharmaceutically acceptable salt thereof, wherein G is ¹ Is CR ³ ；R ³ As defined in formula (I); preferably, R ³ Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; more preferably, R ³ Is C _1-6 Alkoxy or C _1-6 HaloalkoxyA group; most preferably, R ³ Is C _1-6 An alkoxy group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), or formula (V-4), or a pharmaceutically acceptable salt thereof, wherein G is ¹ Is CR ³ ；R ³ Is C _1-6 Alkoxy, preferably methoxy.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof is a compound represented by the formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) ⁴ And R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; preferably, R ⁴ And R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ⁴ And R ⁶ Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III), formula (IV-1), formula (IV-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Selected from hydrogen atom, halogen, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy and-NR ^5a R ^5b Wherein said C _1-6 Alkyl and C _1-6 Alkoxy is independently selected from halogen, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy, amino, 3-to 8-membered cycloalkyl, and 3-to 8-membered heterocyclyl; r ^5a And R ^5b Are the same or different, andeach independently selected from hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ⁵ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; more preferably, R ⁵ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group; further preferably, R ⁵ Is C _1-6 A haloalkoxy group; most preferably, R ⁵ Is difluoromethoxy.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (IV-1) or formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R is ^w is-NR ^w1 R ^w2 ；R ^w1 Is selected from C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo; r is ^w2 Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 8 membered cycloalkyl wherein said C _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo;

preferably, R ^w1 Is selected from C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens; r ^w2 Selected from hydrogen atoms, C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens;

more preferably, R ^w1 Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl; r is ^w2 Is a hydrogen atom;

further preferably, R ^w1 Is a 3 to 8 membered cycloalkyl group; r is ^w2 Is a hydrogen atom;

most preferably, R ^w1 Is cyclopropyl; r ^w2 Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (III), formula (IV-1), formula (IV-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein R is ^w1 Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo; r ^w2 Selected from hydrogen atom, C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo;

preferably, R ^w1 Is selected from C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens; r is ^w2 Selected from hydrogen atom, C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens;

further preferably, R ^w1 Is a 3 to 8 membered cycloalkylA group; r is ^w2 Is a hydrogen atom;

most preferably, R ^w1 Is cyclopropyl; r ^w2 Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (IV-1) or formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R is ^w is-NHR ^w1 ；R ^w1 Is selected from C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo;

preferably, R ^w1 Is selected from C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens;

more preferably, R ^w1 Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl;

further preferably, R ^w1 Is a 3 to 8 membered cycloalkyl group;

most preferably, R ^w1 Is cyclopropyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III), formula (IV-1), formula (IV-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein R is ^w2 Is a hydrogen atom; r ^w1 Is selected from C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo;

preferably, R ^w2 Is a hydrogen atom；R ^w1 Is selected from C _1-6 Alkyl and 3 to 8 membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens;

more preferably, R ^w2 Is a hydrogen atom; r is ^w1 Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl;

more preferably, R ^w2 Is a hydrogen atom; r ^w1 Is a 3 to 8 membered cycloalkyl group;

most preferably, R ^w2 Is a hydrogen atom; r is ^w1 Is cyclopropyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (IV-1) or formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R is ^w is-NR ^w3 -, wherein the N atom is as defined above for R ⁵ Together form a 5-to 6-membered heterocyclyl; r is ^w3 Is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl and 3 to 8-membered cycloalkyl, wherein said C is _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl;

preferably, R ^w3 Is C _1-6 A haloalkyl group;

more preferably, R ^w3 is-CH ₂ CF ₃ 。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein R is ^w3 Is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl and 3 to 8-membered cycloalkyl, wherein said C _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; preferably, R ^w3 Is C _1-6 A haloalkyl group; more preferably, R ^w3 is-CH ₂ CF ₃ 。

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein n is 1.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (II), the general formula (V-1) or the general formula (V-2), or a pharmaceutically acceptable salt thereof, wherein m is 0.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (V-1) or formula (V-2), or a pharmaceutically acceptable salt thereof, wherein R ^y Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy and amino; preferably, R ^y Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^y Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (V-1) or formula (V-2), or a pharmaceutically acceptable salt thereof, wherein n is 1; and/or, R ^y Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring a is a 6-membered heterocyclyl; preferably, ring a is selected from morpholinyl, piperidinyl, piperazinyl and tetrahydropyridinyl; more preferably, ring a is morpholinyl or piperazinyl.

In some preferred embodiments of the present disclosure, the compound of formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered heterocyclic group containing at least one nitrogen atom; preferably, ring a is selected from piperidinyl, piperazinyl and tetrahydropyridinyl; more preferably, ring a is piperazinyl.

In some preferred embodiments of the present disclosure, the compound of formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein

Is composed of

Is a single or double bond; m ₂ Selected from C, CR ¹³ And N; r ¹³ As defined in the general formula (IV-1); preferably, the first and second electrodes are formed of a metal,

is selected from

More preferably, the amount of the organic solvent is,

is composed of

In some preferred embodiments of the present disclosure, the compound of formula (IV), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein each R is ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, oxo, and 3 to 8-membered cycloalkyl; preferably, each R ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 An alkoxy group; more preferably, each R ¹³ Are the same or different and are each independently selected from hydrogenAtom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (IV-2), formula (V-2) or formula (V-4), or a pharmaceutically acceptable salt thereof, wherein R is ¹⁴ Is C _1-6 Alkyl or C _1-6 A haloalkyl group; preferably, R ¹⁴ Is C _1-6 An alkyl group; more preferably, R ¹⁴ Is methyl or propyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ⁷ Is C _1-6 Alkyl or- (CR) ¹⁰ R ¹¹ ) _r R ^c (ii) a Wherein said C _1-6 Alkyl is optionally selected from halogen, cyano, hydroxy, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; r ^c Is 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl, wherein said 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl is each independently optionally selected from halogen, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo; r ¹⁰ And R ¹¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; r is 1,2 or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ⁷ Is- (CH) ₂ ) _r R ^c ；R ^c Is a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is 1,2 or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ⁷ Is- (CH) ₂ ) _r R ^c ；R ^c Is morpholinyl; r is 1,2 or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein R ⁷ Is- (CH) ₂ ) _r R ^c ；R ^c Is morpholinyl or piperazinyl, said morpholinyl and piperazinyl being each independently optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is 1,2 or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ⁷ Is- (CH) ₂ ) _r R ^c ；R ^c Is morpholinyl or piperazinyl, said morpholinyl and piperazinyl each independently optionally being substituted by one or more C _1-6 Alkyl substituted; r is 2.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, R ⁸ And R ⁹ Are the same or different and are each independently a hydrogen atom and C _1-6 An alkyl group; wherein said C _1-6 Alkyl is optionally selected from halogen, cyano, hydroxy, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; or R ⁸ And R ⁹ Together with the attached N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, cyano, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, R ⁸ And R ⁹ Are the same or different, andeach independently selected from hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; or R ⁸ And R ⁹ Together with the linking N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents in the alkoxy group.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, R ⁸ And R ⁹ Together with the linking N atom to form

R ⁰ Is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; preferably, R ⁰ Is C _1-6 An alkyl group; more preferably, R ⁰ Is a methyl group.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II), the general formula (III), the general formula (IV-1), the general formula (IV-2), the general formula (V-1), the general formula (V-2), the general formula (V-3) or the general formula (V-4), or a pharmaceutically acceptable salt thereof, wherein r is 1,2 or 3, preferably r is 2.

In some preferred embodiments of the present disclosure, the compound of formula (IV), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein L is O.

In some preferred embodiments of the present disclosure, the compound of formula (IV), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein r is 2 and L is O.

In some preferred embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3) or formula (V-4) or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1; preferably, t is 0.

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein W ¹ Is CR ^a ；W ² Is CR ^d ；R ^a And R ^d Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r ¹ Is selected from-O-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；R ⁷ Is- (CH) ₂ ) _r R ^c ；R ⁸ And R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; or R ⁸ And R ⁹ Together with the linking N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r ^c Is a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is 2; r ² Is a hydrogen atom; g ¹ Is CR ³ ；R ³ Is C _1-6 An alkoxy group; r ⁴ And R ⁶ Are each a hydrogen atom; x is O or-NR ^b ；R ^b Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl; r ^w3 Is C _1-6 A haloalkyl group; n is 1; r is ^y Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein W ¹ Is CR ^a ；W ² Is CR ^d ；R ^a And R ^d Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 Alkyl halidesA base; r ¹ Is selected from-O-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；R ⁷ Is- (CH) ₂ ) _r R ^c ；R ⁸ And R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; or R ⁸ And R ⁹ Together with the linking N atom form a 3-to 8-membered heterocyclyl, said 3-to 8-membered heterocyclyl being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is ^c Is a 3 to 8 membered heterocyclyl, wherein said 3 to 8 membered heterocyclyl is optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is 2; r ² Is a hydrogen atom; g ¹ Is CR ³ ；R ³ Is C _1-6 An alkoxy group; r ⁵ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group; r ⁴ And R ⁶ Are each a hydrogen atom; x is O or-NR ^b ；R ^b Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl; r ^w1 Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl; r ^w2 Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (V-1) or a pharmaceutically acceptable salt thereof, wherein W is ¹ Is CR ^a ；W ² Is CR ^d ；R ^a And R ^d Are each a hydrogen atom; r ² Is a hydrogen atom; x is-NR ^b ；R ^b Is C _1-6 An alkyl group; g ¹ Is CR ³ ；R ³ Is C _1-6 An alkoxy group; r ⁴ And R ⁶ Are each a hydrogen atom; r ^w3 Is C _1-6 A haloalkyl group; n is 1; m is 0; ring a is a 6-membered heterocyclic group containing at least one nitrogen atom; r is 2; l is O; t is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V-2) or a pharmaceutically acceptable salt thereof, wherein W ¹ Is CR ^a ；W ² Is CR ^d ；R ^a And R ^d Are each a hydrogen atom; r ² Is hydrogenAn atom; x is-NR ^b ；R ^b Is C _1-6 An alkyl group; g ¹ Is CR ³ ；R ³ Is C _1-6 An alkoxy group; r ⁴ And R ⁶ Are each a hydrogen atom; r ^w3 Is C _1-6 A haloalkyl group; n is 1; m is 0; ring a is a 6-membered heterocyclic group containing at least one nitrogen atom; r is 2; l is O; t is 0; r ¹⁴ Is C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (V-3) or a pharmaceutically acceptable salt thereof, wherein W ¹ Is CR ^a ；W ² Is CR ^d ；R ^a And R ^d Are each a hydrogen atom; r is ² Is a hydrogen atom; x is-NR ^b ；R ^b Is C _1-6 An alkyl group; g ¹ Is CR ³ ；R ³ Is C _1-6 An alkoxy group; r is ⁴ And R ⁶ Are each a hydrogen atom; r is ⁵ Is C _1-6 A haloalkoxy group; r ^w1 Is a 3 to 8 membered cycloalkyl group; r is ^w2 Is a hydrogen atom; ring a is a 6-membered heterocyclic group containing at least one nitrogen atom; r is 2; l is O; t is 0.

In some preferred embodiments of the present disclosure, the compound of formula (V-4) or a pharmaceutically acceptable salt thereof, wherein W ¹ Is CR ^a ；W ² Is CR ^d ；R ^a And R ^d Are each a hydrogen atom; r is ² Is a hydrogen atom; x is-NR ^b ；R ^b Is C _1-6 An alkyl group; g ¹ Is CR ³ ；R ³ Is C _1-6 An alkoxy group; r ⁴ And R ⁶ Are each a hydrogen atom; r ⁵ Is C _1-6 A haloalkoxy group; r ^w1 Is a 3 to 8 membered cycloalkyl group; r is ^w2 Is a hydrogen atom; ring a is a 6-membered heterocyclic group containing at least one nitrogen atom; r is 2; l is O; t is 0; r ¹⁴ Is C _1-6 An alkyl group.

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

another aspect of the present disclosure provides a compound represented by the general formula (IV-1A):

wherein:

PG is an amino protecting group; preferably tert-butoxycarbonyl;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ^w T and r are as defined in the general formula (IV-1).

Another aspect of the present disclosure provides a compound represented by the general formula (V-1A):

wherein:

PG is an amino protecting group; preferably tert-butoxycarbonyl;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ 、R ⁶ 、R ¹³ 、R ^w3 、R ^y M, n, t and r are as defined in the general formula (V-1).

Another aspect of the present disclosure provides a compound represented by the general formula (V-3A):

wherein:

PG is an amino protecting group; preferably tert-butoxycarbonyl;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ^w1 、R ^w2 T and r are as defined in the general formula (V-3).

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

another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising:

carrying out coupling reaction on the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IB) or the salt thereof to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

X ¹ is halogen; preferably Br;

W ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ to R ⁶ And R ^w As defined in formula (I).

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

a compound shown in a general formula (IA) or a salt thereof and a compound shown in a general formula (IIB) or a salt thereof are subjected to coupling reaction to obtain a compound shown in a general formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

X ¹ is halogen; preferably Br;

W ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ 、R ⁶ 、R ^y 、R ^w3 n and m are as defined in formula (II).

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

carrying out coupling reaction on the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IIIB) or the salt thereof to obtain the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof,

wherein:

X ¹ is halogen; preferably Br;

W ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ to R ⁶ 、R ^w1 And R ^w2 As defined in formula (III).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IV), or a pharmaceutically acceptable salt thereof, comprising:

the compound shown in the general formula (IVA) or the salt thereof and the compound shown in the general formula (IB) or the salt thereof are subjected to coupling reaction to obtain the compound shown in the general formula (IV) or the pharmaceutically acceptable salt thereof,

wherein:

X ¹ is halogen; preferably Br;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ^w Q and r are as defined in formula (IV).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, which comprises:

PG is removed from the compound shown in the general formula (IV-1A) or the salt thereof to obtain the compound shown in the general formula (IV-1) or the pharmaceutically acceptable salt thereof,

wherein:

PG is an amino protecting group, preferably tert-butoxycarbonyl;

ring A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ^w T and r are as defined in the general formula (IV-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, which comprises:

nucleophilic substitution reaction is carried out on the compound shown in the general formula (IV-1) or pharmaceutically acceptable salt thereof and the compound shown in the general formula (IVB) or salt thereof to obtain the compound shown in the general formula (IV-2) or pharmaceutically acceptable salt thereof,

wherein:

X ² is halogen; preferably iodine;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ¹⁴ 、R ^w T and r are as defined in the general formula (IV-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof, which comprises:

removing PG from the compound represented by the general formula (V-1A) or a salt thereof to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

wherein:

PG is an amino protecting group, preferably tert-butoxycarbonyl;

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof, which comprises:

nucleophilic substitution reaction is carried out between the compound shown in the general formula (V-1) or the pharmaceutically acceptable salt thereof and the compound shown in the general formula (IVB) or the salt thereof to obtain the compound shown in the general formula (V-2) or the pharmaceutically acceptable salt thereof,

wherein:

X ² is halogen; preferably iodine;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ 、R ⁶ 、R ¹³ 、R ¹⁴ 、R ^w3 、R ^y M, n, t and r are as defined in the general formula (V-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (V-3) or a pharmaceutically acceptable salt thereof, the method comprising:

removing PG from the compound represented by the general formula (V-3A) or a salt thereof to obtain a compound represented by the general formula (V-3) or a pharmaceutically acceptable salt thereof,

wherein:

PG is an amino protecting group, preferably tert-butoxycarbonyl;

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (V-4) or a pharmaceutically acceptable salt thereof, which comprises:

nucleophilic substitution reaction is carried out between the compound shown in the general formula (V-3) or the pharmaceutically acceptable salt thereof and the compound shown in the general formula (IVB) or the salt thereof to obtain the compound shown in the general formula (V-4) or the pharmaceutically acceptable salt thereof,

wherein:

X ² is halogen; preferably iodine;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ¹⁴ 、R ^w1 、R ^w2 T and r are as defined in the general formula (V-4).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4), 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 compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (V-3), general formula (V-4) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for inhibiting SIK2 and/or SIK3, preferably in the preparation of a medicament for inhibiting SIK 2.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4), 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 disease or disorder selected from the group consisting of inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with hypersecretion of TNF α, interferons, IL-6, IL-12, and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and diseases associated with abnormal angiogenesis; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease; more preferably, wherein said inflammatory disease or autoimmune disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis.

The present disclosure further relates to a method of inhibiting SIK2 and/or SIK3 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder selected from the group consisting of inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with excessive secretion of TNF α, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases and abnormal angiogenesis-related diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease; more preferably, wherein said inflammatory disease or autoimmune disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis.

The present disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for inhibiting SIK2 and/or SIK3.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), formula (V-3), formula (V-4) and table a 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 selected from the group consisting of inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with excessive secretion of TNF α, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases and abnormal angiogenesis-related diseases; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease; more preferably, wherein said inflammatory disease or autoimmune disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis.

The disease or disorder is preferably a SIK2 and/or SIK3 mediated disease or disorder; more preferably a SIK2 mediated disease or disorder.

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

The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, the active compound is preferably in unit dosage form, or in such a way that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose 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: 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 active compound.

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 which 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 an 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. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickening agent. Sweetening agents such as those set forth above, 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 oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

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 the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into 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 therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular 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, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or 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 aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably alkyl (i.e., C) containing 1 to 12 (e.g., 1,2,3,4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl groups). <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3 </xnotran>Ethylhexyl group, 2-diethylpentyl group, n-decyl group, 3-diethylhexyl group, 2-diethylhexyl group, and various branched chain isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl radicals (i.e. C) containing from 2 to 12, for example 2,3,4, 5, 6, 7, 8, 9, 10, 11 and 12, carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl (i.e., C) groups containing 2 to 12 (e.g., 2,3,4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkynyl), more preferably an alkynyl group containing 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, 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 or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms (i.e., 3 to 20 membered cycloalkyl groups), preferably 3 to 14 (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (i.e., 3 to 14 membered cycloalkyl groups), preferably 3 to 8 (e.g., 3,4, 5, 6, 7 and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds (i.e., a 5 to 20 membered spirocycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds (i.e., a 5 to 20 membered fused cyclic alkyl). Preferably 6 to 14 (i.e. 6 to 14 fused cycloalkyl) members, more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 fused cycloalkyl) members. Bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups may be classified according to the number of constituent rings, and are preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, and 6-membered/6-membered bicyclic fused cycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 membered bridged cycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered bridged cycloalkyl). They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, according to the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the rings attached together with the parent structure are cycloalkyl, non-limiting examples of which include

Etc.; preferably, it is

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

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but which does not include a cyclic portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon (i.e., a 3 to 20 membered heterocyclyl). Preferably 3 to 12 (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3,4, 5, 6, 7 and 8), of which 1-3 (e.g., 1,2 and 3) are heteroatoms (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds (i.e., 5 to 20 membered spiroheterocyclyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spiroheterocyclyl). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5 to 20 membered fused heterocyclyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered fused heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5 to 14 membered bridged heterocyclyl). Preferably 6 to 14 (i.e. 6 to 14 bridged heterocyclyl) and more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 bridged heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes heterocyclyl groups (including monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl groups) as described above fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

and the like.

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

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

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

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

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

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived from the parent ring atom by the removal of one hydrogen atom, or those derived from the parent ring atom by the removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "amino protecting group" is a group that is easily removed and is introduced so that the amino group remains unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsiloxy) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro.

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

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

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

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

The term "aryloxy" refers to aryl-O-wherein aryl 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 "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "= O".

The term "carbonyl" refers to C = O.

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

The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the disclosure, replacing hydrogen with "deuterium" or "tritium", or ¹⁸ F-fluorine labeling: ( ¹⁸ Isotope of F) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enriched carbon (C) ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. For all carbon-carbon double bonds, both Z-and E-forms are included, even if only one configuration is named. 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. One isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to give the pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

Compounds described in the disclosureIn the chemical structure of (1), a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be made of

Or

Or at the same time contain

And

two configurations.

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

"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group 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 acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

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 effective for the intended use.

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

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

The term "inflammatory disorder" is meant to include the following diseases or disorders: rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway diseases (e.g., asthma, rhinitis), chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel diseases (e.g., crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., bypass postoperative complications or chronic endotoxin conditions contributing to, for example, chronic heart failure) and related diseases involving cartilage such as articular cartilage. Preferably, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g. asthma), chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease. More preferably, the term refers to rheumatoid arthritis, chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease.

The term "autoimmune disease" is meant to include the following diseases or conditions: obstructive airway diseases, including conditions such as COPD, asthma (e.g. intrinsic asthma, extrinsic asthma, dust asthma, asthma infancy), in particular chronic or refractory asthma (e.g. late asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic Lupus Erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver disease (e.g. autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis), sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (hashimoto and autoimmune thyroiditis), contact dermatitis, inflammatory bowel disease (e.g. crohn's disease and ulcerative colitis), sjogren's syndrome and amyotrophic lateral sclerosis. Preferably, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes and inflammatory bowel disease.

The term "diseases involving impairment of cartilage turnover" includes the following diseases or conditions: osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful dystrophy, tietz syndrome or costal chondritis, fibromyalgia, osteochondral spondylitis, neurogenic or neurogenic arthritis, arthropathies, endemic arthritis such as endemic osteoarthritis, mselai's (mselini) disease, and handidu's disease; degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

The term "diseases involving impairment of bone turnover" includes the following diseases or conditions: osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticoid-induced osteoporosis, and juvenile osteoporosis), osteoporosis through neoplastic bone marrow disorders, osteopenia, hormone deficiency (vitamin D deficiency, male and female hypogonadism), hormone excess (hyperprolactinemia, excess glucocorticoid, hyperthyroidism, hyperparathyroidism), paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, hypophosphatasia.

The term "diseases associated with excessive secretion of TNF, interferon, IL-12 and/or IL-23" includes conditions such as: systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or crohn's disease.

The term "respiratory disease" refers to a disease that affects organs involved in breathing, such as the nose, pharynx, larynx, eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., septum and intercostal) and nerves. Preferably, examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocarbonic acid hyperventilation (isocapanic hyperventilation), childhood asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema), pulmonary hypertension, interstitial pulmonary fibrosis and/or airway inflammation, cystic fibrosis and hypoxia.

The term "proliferative disease" refers to conditions such as: cancer, myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis), and fibrosis. Preferably, the term refers to cancer.

The term "cancer" includes leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors of the embryo, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastoma, neuroblastoma, germ cell tumors, teratomas, gastric cancer, esophageal cancer, liver cancer, cholangiocellular carcinoma, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, endometrial cancer, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, sarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, gastrointestinal stromal tumors (GIST), kaposi's sarcoma, and pediatric cancer.

Synthesis of the compounds of the present disclosure

In order to achieve the purpose of the present disclosure, the following technical solutions are adopted in the present disclosure:

scheme one

The invention discloses a method for preparing a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IB) or the salt thereof are subjected to coupling reaction under the alkaline condition and in the presence of a catalyst to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

X ¹ is halogen; preferably Br;

W ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ and R ^w As defined in formula (I).

Scheme two

The invention discloses a method for preparing a compound shown as a general formula (II) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

a compound shown in a general formula (IA) or a salt thereof and a compound shown in a general formula (IIB) or a salt thereof are subjected to coupling reaction under alkaline conditions and in the presence of a catalyst to obtain a compound shown in a general formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

X ¹ is halogen; preferably Br;

Scheme three

A process for preparing a compound of the general formula (III) or a pharmaceutically acceptable salt thereof, which comprises:

the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IIIB) or the salt thereof are subjected to coupling reaction under alkaline conditions and in the presence of a catalyst to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof,

wherein:

X ¹ is halogen; preferably Br;

Scheme four

The invention discloses a method for preparing a compound shown as a general formula (IV) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

wherein:

X ¹ is halogen; preferably Br;

Scheme five

Disclosed is a method for producing a compound represented by the general formula (IV-1) below or a pharmaceutically acceptable salt thereof, which comprises:

removing PG from the compound represented by the general formula (IV-1A) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,

wherein:

PG is an amino protecting group; preferably tert-butoxycarbonyl;

Scheme six

A process for producing a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, which comprises:

nucleophilic substitution reaction is carried out on the compound shown in the general formula (IV-1) or the pharmaceutically acceptable salt thereof and the compound shown in the general formula (IVB) or the salt thereof under the alkaline condition to obtain the compound shown in the general formula (IV-2) or the pharmaceutically acceptable salt thereof,

wherein:

X ² is halogen; preferably iodine;

ring A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ¹⁴ 、R ^w T and r are as defined in the general formula (IV-2).

Scheme seven

Disclosed is a method for producing a compound represented by the general formula (V-1) below or a pharmaceutically acceptable salt thereof, which comprises:

removing PG from a compound represented by the general formula (V-1A) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

wherein:

PG is an amino protecting group, preferably tert-butoxycarbonyl;

ring A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ 、R ⁶ 、R ¹³ 、R ^w3 、R ^y M, n, t and r are as defined in the general formula (V-1).

Scheme eight

A process for producing a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof, which comprises:

nucleophilic substitution reaction is carried out on the compound shown in the general formula (V-1) or pharmaceutically acceptable salt thereof and the compound shown in the general formula (IVB) or salt thereof under alkaline conditions to obtain the compound shown in the general formula (V-2) or pharmaceutically acceptable salt thereof,

wherein:

X ² is halogen, preferably iodine;

Scheme nine

A process for producing a compound represented by the general formula (V-3) or a pharmaceutically acceptable salt thereof, which comprises:

removing PG from the compound represented by the general formula (V-3A) or a salt thereof under acidic conditions to obtain a compound represented by the general formula (V-3) or a pharmaceutically acceptable salt thereof,

wherein:

PG is an amino protecting group, preferably tert-butoxycarbonyl;

Scheme ten

A process for producing a compound represented by the general formula (V-4) or a pharmaceutically acceptable salt thereof, which comprises:

nucleophilic substitution reaction is carried out on the compound shown in the general formula (V-3) or the pharmaceutically acceptable salt thereof and the compound shown in the general formula (IVB) or the salt thereof under the alkaline condition to obtain the compound shown in the general formula (V-4) or the pharmaceutically acceptable salt thereof,

wherein:

X ² is halogen, preferably iodine;

ring A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ¹⁴ 、R ^w1 、R ^w2 T and r are as defined in the general formula (V-4).

The reagents that provide basic conditions in the above synthetic schemes include organic and inorganic bases, including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate (potassium acetate), sodium tert-butoxide, potassium tert-butoxide, or 1, 8-diazabicycloundecen-7-ene; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably, the agent that provides basic conditions is potassium acetate or potassium carbonate.

Reagents that provide acidic conditions in the above synthetic schemes include, but are not limited to, trifluoroacetic acid, hydrochloric acid, 1, 4-dioxane solution of hydrogen chloride, formic acid, acetic acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, me ₃ SiCl and TMSOTf; preferably, the agent that provides acidic conditions is a1, 4-dioxane solution of hydrogen chloride.

The catalyst used in the above synthesis scheme includes, but is not limited to tetrakis (triphenylphosphine) palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II), 1 '-bis (dibenzylphosphine) dichlorodiamondra, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, 1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, tris (dibenzylideneacetone) dipalladium, etc., and preferably, the catalyst used is [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium.

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

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not 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). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

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

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

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

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD and Waters HPLC e2695-2489.

Chiral HPLC analytical determination Agilent 1260 DAD HPLC was used.

High Performance liquid preparation preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281.

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

CombiFlash flash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate adopts a cigarette platform 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.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenator.

The hydrogenation reaction is usually carried out by vacuum pumping, hydrogen filling and repeated operation for 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the n-hexane/ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

N-cyclopropyl-2- (difluoromethoxy) -6-methoxy-4- (2-methyl-6- (2-morpholinoethoxy) -2H-indazol-3-yl) benzamide 1

First step of

4- (2- ((2-methyl-2H-indazol-6-yl) oxy) ethyl) morpholine 1b

The compound 6-bromo-2-methyl-2H-indazole 1a (1.05g, 4.97mmol, tokyo pharmaceutical technology, ltd.) was dissolved in 1, 4-dioxane (10 mL), and 2-morpholinoethanol (1.30g, 9.91mmol, tokyo pharmaceutical technology, ltd.) was added, sodium tert-butoxide (0.58g, 6.03mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (520mg, 0.90mmol), heated to 90 ℃ under nitrogen, and stirred for 16 hours. Cooled to room temperature, concentrated and purified by silica gel column chromatography with eluent system A to give the title compound 1b (548 mg, yield: 42.2%).

MS m/z(ESI):262.2[M+1]。

Second step of

Compound 1b (36mg, 0.14mmol) was dissolved in N, N-dimethylacetamide (3 mL), and the compound 4-bromo-N-cyclopropyl-2- (difluoromethoxy) -6-methoxybenzamide 1c (50mg, 0.15mmol, prepared using the method disclosed in intermediate 11 on page 153 of the specification in patent application WO2019238424 A1), potassium acetate (35mg, 0.36mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (10mg, 0.01mmol), heated to 120 ℃ under nitrogen and stirred for 3 hours. Cooled to room temperature, and separated and purified by high performance liquid chromatography (Waters-2555, column: sharpSil-T C18 50 x 250mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 11 min gradient: 37% -48%, flow rate: 80 mL/min) to give the title compound 1 (15 mg, yield: 21.1%).

MS m/z(ESI):517.2[M+1]。

1H NMR(500MHz,DMSO-d ₆ )δ8.43(d,1H),7.48(d,1H),7.19(d,1H),7.04-6.96(m,2H),6.78(dt,1H),4.21-4.07(m,5H),3.87(s,3H),3.77(s,2H),3.59(t,4H),2.80(dt,1H),2.74(q,2H),0.67(d,3H),0.45(d,3H)。

Example 2

8-methoxy-6- (2-methyl-6- (2-morpholinoethoxy) -2H-indazol-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 2

First step of

Compound 1b (50mg, 0.19mmol) was dissolved in N, N-dimethylacetamide (3 mL), and the compound 6-bromo-8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 2a (65mg, 0.19mmol, prepared using the method disclosed in patent application WO2019238424A1 as intermediate 39 on page 162), potassium acetate (50mg, 0.51mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (14mg, 0.01mmol) was added, and the mixture was heated to 120 ℃ under nitrogen and stirred for 3 hours. Cooled to room temperature, and separated and purified by high performance liquid chromatography (Waters-2555, column: sharpSil-T C18 50 x 250mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 12 min gradient: 37% -48%, flow rate: 80 mL/min) to give the title compound 2 (24 mg, yield: 24.2%).

MS m/z(ESI):519.3[M+1]。

1H NMR(500MHz,DMSO-d ₆ )δ7.55(d,1H),7.20(d,1H),7.15(d,1H),7.00(d,1H),6.77(dd,1H),4.36(q,2H),4.14(s,5H),3.87(s,3H),3.65(t,2H),3.59(t,4H),3.02(t,2H),2.74(t,2H),2.49(d,4H)。

Example 3

8-methoxy-6- (2-methyl-6- (4-methylpiperazin-1-yl) -2H-indazol-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 3

First step of

2-methyl-6- (4-methylpiperazin-1-yl) -2H-indazole 3a

Methylpiperazine (0.36g, 3.59mmol, shanghai Biao pharmaceutical technology Co., ltd.) was dissolved in toluene (10 mL), and compound 1a (0.50g, 2.37mmol, shanghai Biao pharmaceutical technology Co., ltd.), sodium tert-butoxide (0.34g, 3.54mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (82mg, 0.14mmol), tris (dibenzylideneacetone) dipalladium (43mg, 0.05mmol) were added, and the mixture was heated to 100 ℃ under nitrogen atmosphere and stirred for 16 hours. After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3a (470 mg, yield: 86.1%).

MS m/z(ESI):231.1[M+1]。

Second step of

Compound 3a (50mg, 0.22mmol) was dissolved in N, N-dimethylacetamide (3 mL), compound 2a (75mg, 0.15mmol), potassium acetate (55mg, 0.56mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (16mg, 0.02mmol) were added and heated to 120 ℃ under nitrogen and stirred for 3 hours. Cooled to room temperature, and separated and purified by high performance liquid chromatography (Waters-2555, column: sharpSil-T C18 50 x 250mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 12 min gradient: 34% -46%, flow rate: 80 mL/min) to give the title compound 3 (52 mg, yield: 49.1%).

MS m/z(ESI):488.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ7.51(d,1H),7.19(d,1H),7.14(d,1H),7.01(dd,1H),6.82(d,1H),4.36(q,2H),4.12(s,3H),3.87(s,3H),3.65(t,2H),3.15(t,4H),3.02(t,H),2.54-2.51(m,4H),2.26(s,3H)。

Example 4

8-methoxy-6- (2-methyl-6- (2- (4-propylpiperazin-1-yl) ethoxy) -2H-indazol-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4

First step of

6-bromo-3-iodo-2-methyl-2H-indazole 4b

6-bromo-2-methyl-2H-indazole 4a (6.83g, 32.37mmol, shao Yuan chemical technology (Shanghai) Co., ltd.) was dissolved in methylene chloride (90 mL), and [ bis (trifluoroacetoxy) iodo ] benzene (16.70g, 38.83mmol, shao Yuan chemical technology (Shanghai) Co., ltd.) and pyridine (3.84g, 48.55mmol) were added thereto, and after stirring at room temperature for 0.5 hour, iodine (9.85g, 38.81mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. After concentration, purification by silica gel column chromatography with eluent system B gave the title compound 4B (9.5 g, yield: 87.1%).

MS m/z(ESI):338.8[M+1]。

Second step of

6- (6-bromo-2-methyl-2H-indazol-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4d

Compound 4b (2.7g, 8.01mmol) was dissolved in 1, 4-dioxane (90 mL), 8-methoxy-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- (2,2,2-trifluoroethyl) -3,4-dihydroisoquinolin-1 (2H) -one 4c (3.70g, 9.61mmol, prepared using the method disclosed in intermediate 3 on page 70 of the description of patent application WO2020239660A 1), water (18 mL), cesium carbonate (7.83g, 24.03mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (586mg, 0.80mmol) was added and heated to 100 ℃ under nitrogen and stirred for 4 hours. Cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 4d (3.7 g, yield: 98.6%).

MS m/z(ESI):470.0[M+1]。

The third step

8-methoxy-6- (2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-2H-indazol-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4e

Compound 4d (2.0g, 4.27mmol) was dissolved in 1, 4-dioxane (60 mL), pinacol diboron ester (1.19g, 4.69mmol), potassium acetate (1.25g, 12.74mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (312mg, 0.43mmol) were added, and the mixture was heated to 90 ℃ under nitrogen atmosphere and stirred for 5 hours. Cooled to room temperature, concentrated and purified by silica gel column chromatography with eluent system A to give the title compound 4e (2.2 g, yield: 99.9%).

MS m/z(ESI):516.1[M+1]。

The fourth step

6- (6-hydroxy-2-methyl-2H-indazol-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4f

Compound 4e (2.2g, 4.27mmol) was dissolved in tetrahydrofuran (50 mL), dropwise added hydrogen peroxide (1.45g, 12.79mmol,30% strength) under ice-bath, stirred for 10 minutes, added sodium hydroxide solution (8mL, 0.5M), stirred at room temperature for 1 hour, added water (50 mL), extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 4f (850 mg, yield: 49.1%).

MS m/z(ESI):406.1[M+1]。

The fifth step

4- (2- ((3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -2-methyl-2H-indazol-6-yl) oxy) ethyl) piperazine-1-carboxylic acid tert-butyl ester 4H

The compound 4f (2454mg, 0.60mmol) was dissolved in N, N-dimethylacetamide (5 mL), and 4g (200mg, 0.68mmol, shanghai Haohnhong biomedical science and technology Co., ltd.) of tert-butyl 4- (2-bromoethyl) piperazine-1-carboxylate and cesium carbonate (600mg, 1.84mmol) were added and the mixture was heated to 80 ℃ and stirred for 2 hours. After cooling to room temperature, water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the title compound was obtained for 4h (360 mg, yield: 96.4%) and the product was used in the next reaction without purification.

MS m/z(ESI):618.2[M+1]。

The sixth step

8-methoxy-6- (2-methyl-6- (2- (piperazin-1-yl) ethoxy) -2H-indazol-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4i

Compound 4h (360mg, 0.58mmol) was added to a solution of hydrogen chloride in 1, 4-dioxane (2.9mL, 4M) and stirred at room temperature for 1 h. After concentration under reduced pressure, the title compound 4i (322 mg, yield: 99.7%) was obtained and used in the next reaction without purification.

MS m/z(ESI):518.2[M+1]。

Step seven

Compound 4i (322mg, 0.58mmol) was added to acetonitrile (30 mL), potassium carbonate (400mg, 2.89mmol) and 1-iodopropane (200mg, 1.18mmol) were added, and the mixture was heated to 80 ℃ and stirred for 16 hours. Cooled to room temperature, concentrated and then purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C1830 x 150mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 13 min acetonitrile gradient: 34% -47%, flow rate: 30 mL/min) to give the title compound 4 (140 mg, yield: 43.0%).

MS m/z(ESI):560.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ7.55(d,1H),7.20(s,1H),7.14(s,1H),6.99(d,1H),6.76(dd,1H),4.36(q,2H),4.13(d,5H),3.87(s,3H),3.65(t,2H),3.02(t,2H),2.73(t,2H),2.39(s,4H),2.22(q,2H),1.45-1.39(m,2H),1.23(d,4H),0.84(t,3H)。

Biological evaluation

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

Test example 1 inhibition of human SIK1 kinase by Compounds of the disclosure

Experimental materials and instruments

SIK1 enzyme (Carna, 02-131)

2.AMARA(GL,226536)

3.DMSO(Sigma,D2650)

4.96-well plate (Corning, 3365)

5.384-well plate (Corning, 3573)

6. Staurosporine (MCE HY-15141)

7.ATP(Sigma,2383-5g)

8. Magnesium chloride (Sigma, M2670-500 g)

9.DTT(Sigma，D0632-10g)

10.Triton X-100(Sigma，T9284-100 mL)

11.HEPES(Gibco，11344-041)

Brij-35 solution (Sigma, B4184-100 mL)

13.EDTA(Gibco，15575-038)

14. Coating Reagent #3 (Coating Reagent #3, perkin Elmer)

15.Caliper EZ Reader No.2(Perkin Elmer)

Precision automatic liquid-transfering system (BioTek)

17. Constant temperature box (Shanghai Boxun)

Second, experimental procedure

SIK1 is a kinase that phosphorylates the substrate AMARA in the presence of ATP. Mobility shift assay (Mobility shift assay) can be used to detect changes in SIK1 enzyme activity. Using FAM fluorescently labeled AMARA as a substrate, AMARA is phosphorylated in the presence of ATP and then carries a phosphate group, which differs by 3 negative charges from the non-phosphorylated substrate. And (3) sucking the reacted liquid into a microfluidic chip, and allowing the AMARA substrate and the product to enter a capillary with an electric field and perform electrophoresis towards the positive electrode. Because the polypeptide product carries phosphate ions and has a high migration rate, the residual substrate and the product are separated by the method, and finally, the peak ratio of the product to the residual substrate is calculated by a fluorescence detection system, so that the change of the enzyme activity is detected.

Diluting 20mM test compound dissolved in 100% DMSO to 500. Mu.M with 100% DMSO, which is a concentration 50 times the highest concentration point of the compound in the reaction system, diluting this concentration of compound 4 times with 100% DMSO serially by 9 concentration points, for a total of 10 concentration points, and blank wells are 100% DMSO. The above serially diluted compounds and 100% DMSO in 1 Xkinase buffer (50mM HEPES, pH7.5, 10mM MgCl ₂ 2mM DTT,0.01% Triton X-100) to a concentration of 5X, and mixing well; add 5. Mu.L of 5 Xconcentration compound to reaction wells, negative control wells (no enzyme) and positive control wells (no compound with enzyme)Add 5. Mu.L 10% DMSO. The SIK1 enzyme was diluted to 2.5-fold concentration (final reaction concentration 18 nM) in 1 Xkinase buffer, and 10. Mu.L of the enzyme dilution was transferred to the reaction system and incubated at room temperature for 10 minutes. AMARA and ATP were diluted to a 2.5-fold concentration (AMARA reaction final concentration of 3. Mu.M, ATP reaction final concentration of 128. Mu.M) in 1 Xkinase buffer, 10. Mu.L of the substrate and ATP solution were transferred to the reaction system, mixed well, reacted at 28 ℃ for 60 minutes, and 25. Mu.L of stop solution (100 mM HEPES, pH7.5, 0.015% Brij-35,0.2% coating reagent #3, 50mM EDTA) was added.

Reading the reaction product on a Caliper instrument, and calculating the obtained value as the inhibition rate according to the following formula: inhibition = (positive control value-test well value)/(positive control value-negative control value) × 100. The curve was fitted on an XLFit version 5.4.0.8 and the compound concentration IC at 50% inhibition was calculated ₅₀ See table 1.

TABLE 1 IC for enzymatic inhibition of human SIK1 by Compounds of the disclosure ₅₀ Value of

Example numbering	IC ₅₀ (nM)	Imax(％)
			1	995	88
2	2592	76
			3	9202	58
4	1592	90

And (4) conclusion: the compounds of the present disclosure have weak inhibitory effect on SIK 1.

Test example 2 inhibition of human SIK2 kinase by Compounds of the disclosure

Experimental materials and instruments

SIK2 enzyme (Promega, VA 7267)

2.ADP-Glo ^TM Kinase reagent (Promega, V9101)

3.DMSO(Sigma,D2650)

4. Magnesium chloride solution (Sigma, M1028-100ML,)

Tris pH7.5 2M (Biyuntian, B548139-0500)

6.Triton X-100(Sigma,T8787-100ML)

7.EGTA(Sigma,E3889-100G)

DTT 2M (Biotechnology, B645939)

9.96-well plate (Corning, 3795)

10.384-orifice plate (Corning, 4513)

11. Sterile pure water (homemade Hengrui Shanghai)

12.15 mL centrifuge tube (Corning)

13. Constant temperature box (Shanghai-Heng scientific instruments Co., ltd.)

PHERAstar FS microplate reader (BMG Labtech)

Second, experimental procedure

SIK2 is a kinase that phosphorylates AMARA, a substrate, in the presence of ATP. The ADP-Glo detection kit is an ADP detection reagent based on a luminescence method, and can be used for detecting the change of the enzyme activity of SIK 2. The operation of the kit is carried out in three steps: 1) AMARA as a substrate, which is phosphorylated in the presence of ATP to produce ADP; 2) After completion of the ADP production reaction, adding an ADP-Glo reagent to terminate the reaction and consume the remaining ATP; 3) Adding a kinase detection reagent to convert ADP into ATP and convert ATP into optical signals in coupled luciferase/luciferin reaction, thereby detecting the change of enzyme activity.

Diluting 20mM of the test compound dissolved in 100% DMSO to 1mM by 100% DMSO, which is a concentration 100 times the highest concentration point of the compound in the reaction system, diluting the compound at this concentration by 4 times by 10 concentration points in 100% DMSO, and making the blank well 100% DMSO. Diluting the serially diluted compounds and 100% (v/v) DMSO in water to 5X concentration by 20 times, and mixing well; mu.L of 5 Xconcentration compound was taken in the reaction wells, and 1. Mu.L of 5% DMSO was added to the negative control wells (no enzyme added) and the positive control wells (no compound added with enzyme). SIK2 enzyme and AMARA were diluted to 2.5-fold concentration in reaction buffer (25mM tris, ph7.5, 0.01% triton X-100,0.5mM egta,5mM magnesium chloride, 2.5mM DTT) (final reaction concentration SIK2:0.37nm AMARA. ATP was diluted to 2.5-fold concentration in the reaction buffer (final reaction concentration: 5. Mu.M), and 2. Mu.L was transferred to the reaction system. The 5. Mu.L reaction was mixed well and incubated at room temperature for 120 minutes. The reaction was stopped by adding 5. Mu.L of ADP-Glo reagent and incubated at room temperature for 40min to deplete the remaining ATP. Then 10. Mu.L of kinase detection reagent was added and incubated at room temperature for 30min. And (4) reading, and calculating the obtained value as an inhibition rate according to the following formula: inhibition =100-100 (testwell number-negative control value)/(positive control value-negative control value). Using Graphpad Prism software to draw an inhibition curve according to each concentration of the compound and the corresponding inhibition rate, and calculating the concentration of the compound when the inhibition rate reaches 50%, namely IC ₅₀ The values are shown in Table 2.

TABLE 2 IC for enzymatic inhibition of human SIK2 by the compounds of this disclosure ₅₀ Value of

Example numbering	IC ₅₀ (nM)	Imax(％)
			1	37	100
2	44	100
			3	75	99
4	36	100

And (4) conclusion: the disclosed compound has a good inhibition effect on SIK 2. By comparing test example 1 with test example 2, it can be seen that the disclosed compound has a selective inhibitory effect on SIK 2.

Test example 3 pharmacokinetic evaluation

1. SD rat test

1. Abstract (abstract)

The drug concentration in plasma of SD rats at different times after gavage (i.g.)/intravenous injection (i.v.) administration of the compound of example 2 and the compound of example 4 was measured by LC/MS method using SD rats as test animals. The pharmacokinetic behavior of the compounds of the present disclosure was studied in SD rats and evaluated for their pharmacokinetic profile.

2. Test protocol

2.1 test drugs

The compound of example 2 and the compound of example 4.

2.2 test animals

16 SD rats, half male and female, were evenly divided into 4 groups, provided by Zhejiang Weitonglihua laboratory animal technology, inc. After fasting overnight, the administration was by gavage and intravenous injection, respectively.

2.3 pharmaceutical formulation

An amount of the compound of example 2 and the compound of example 4 were weighed, respectively, and added with 5% DMSO +5% Tween 80+90% physiological saline to prepare a colorless clear solution (gavage group) of 0.2mg/mL and a colorless clear solution (intravenous group) of 0.2 mg/mL.

2.4 administration of drugs

And (3) intragastric administration group: the dose was 2.0mg/kg and the volume was 10.0mL/kg.

Group for intravenous administration: the dose was 1.0mg/kg and the volume was 5.0mL/kg.

3. Operation of

And (3) intragastric administration group: 0.2mL of blood was collected from the orbit 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after administration, and the blood was centrifuged at 10000rpm for 1 minute (4 ℃) in an EDTA-K2 anticoagulation tube, and the plasma was separated within 1 hour and stored at-20 ℃ for testing. The blood collection to centrifugation process is operated under ice bath condition. Food was consumed 2 hours after dosing.

Group for intravenous administration: blood was collected before administration and 5 minutes after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours, and the group was treated with intragastric administration.

Determination of the content of the test compounds in the plasma of SD rats after administration of drugs at different concentrations: samples of SD rat plasma were taken at 25. Mu.L each time post-dose, 50. Mu.L of camptothecin (100 ng/mL) was added to each sample, and the protein was precipitated with 200. Mu.L of acetonitrile, vortexed for 5 minutes, and centrifuged at 3700rpm for 10 minutes. 30 mu L of supernatant is taken, 120 mu L of water is added, the mixture is mixed evenly, and 0.5 mu L of sample is injected for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

TABLE 3 pharmacokinetic parameters of Compounds of the disclosure

And (4) conclusion: the compound disclosed by the invention has low clearance rate in SD rats, long half-life period and pharmacokinetic advantage.

Claims

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

wherein:

W ¹ is CR ^a Or an N atom;

W ² is CR ^d Or an N atom; provided that W is ¹ And W ² Not being N atoms at the same time;

x is selected from O or-NR ^b ；

R ^A selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkenyl group, alkynyl group, cyano group, nitro group, hydroxyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, cycloalkyloxy group, heterocyclic group, heterocyclyloxy group, oxo group, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl; wherein said alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, oxo, -C (O) R ^f1 、-NR ^g2 R ^h2 、-NHC(O)OR ^f1 、-C(O)NR ^g2 R ^h2 、-S(O) ₂ R ^J1 、-S(O) ₂ NR ^g2 R ^h2 Aryl and heteroaryl, substituted with one or more substituents;

G ¹ is CR ³ Or an N atom;

R ³ 、R ⁴ and R ⁶ The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkenyl groups, alkynyl groups, cyano groups, nitro groups, hydroxy groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, amino groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein said alkenyl groups, alkynyl groups, alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, cyano groups, nitro groups, hydroxy groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, amino groups, oxo groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R ⁵ selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy and-NR ^5a R ^5b Wherein said alkenyl, alkynyl, alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^5a and R ^5b The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

R ^w is-NR ^w1 R ^w2 or-NR ^w3 -；

R ⁷ selected from hydrogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or- (CR) ¹⁰ R ¹¹ ) _r R ^c (ii) a Wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, substituted with one or more substituents；

R ⁸ And R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, substituted with one or more substituents;

or R ⁸ And R ⁹ Together with the attached N atom, form a heterocyclic group optionally selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, substituted with one or more substituents;

R ¹⁰ and R ¹¹ The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, and heterocyclyl;

R ^c is cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is each independently optionally selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, -C (O) R ^f 、-NR ^g1 R ^h1 、-NHC(O)OR ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 In aryl and heteroaryl groupsSubstituted with one or more substituents of (a);

R ^g1 、R ^h1 、R ^g2 and R ^h2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group; wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^g1 And R ^h1 To the bound N atom, R ^g2 And R ^h2 Together with the attached N atom, form a heterocyclyl group, said heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^J and R ^J1 Identical or different and each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

r is 1,2,3,4, 5 or 6.

2. The compound according to claim 1, which is a compound represented by the general formula (II):

wherein:

n is 0, 1 or 2;

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

W ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ 、R ⁶ and R ^w3 As defined in claim 1.

3. The compound according to claim 1, which is a compound represented by the general formula (IV):

wherein:

l is O or S;

ring a is a 3-to 12-membered heterocyclyl;

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

W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ to R ⁶ 、R ^w 、R ^f 、R ^g1 、R ^h1 、R ^J And r is as defined in claim 1.

4. The compound according to claim 1 or 3, which is a compound represented by the general formula (IV-1) or the general formula (IV-2):

wherein:

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

L、W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ to R ⁶ 、R ¹³ 、R ^w 、R ^f And r is as defined in claim 3.

5. The compound according to any one of claims 1 to 4, which is a compound represented by the general formula (V-1) or the general formula (V-2):

wherein:

n is 0, 1 or 2;

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

R ¹⁴ selected from alkyl, haloAlkyl, hydroxyalkyl, cycloalkyl, heterocyclyl and-C (O) R ^f ；

t is selected from 0, 1,2,3 or 4;

L、W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ 、R ⁶ 、R ¹³ 、R ^f 、R ^w3 and r is as defined in claim 3.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein W is ¹ Is CR ^a (ii) a And/or, W ² Is CR ^d ；R ^a And R ^d Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

7. The compound according to any one of claims 1,2 or 6, or a pharmaceutically acceptable salt thereof, wherein

Is composed of

R ¹ 、R ² 、R ^a 、R ^b And R ^d As defined in claim 1.

8. The compound according to any one of claims 1,2, 6 or 7, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is selected from-O-R ⁷ 、-NR ⁸ R ⁹ and-C (O) NR ⁸ R ⁹ ；

R ⁷ Is- (CH) ₂ ) _r R ^c ；

R ⁸ and R ⁹ Are the same or different and are each independently selected from hydrogen atoms、C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; or R ⁸ And R ⁹ Together with the linking N atom form a 3-to 8-membered heterocyclyl group, said 3-to 8-membered heterocyclyl group being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy; r is 1,2 or 3.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R ² Is a hydrogen atom.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is O or-NR ^b ；R ^b Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CR ³ ；R ³ Is C _1-6 An alkoxy group.

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R ⁴ And R ⁶ Are all hydrogen atoms.

13. The compound according to any one of claims 1,3, 4, 6 to 12, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group.

14. The compound according to any one of claims 1,3, 4, 6 to 13, or a pharmaceutically acceptable salt thereof, wherein R ^w is-NHR ^w1 ；R ^w1 Is C _1-6 Alkyl or 3 to 8 membered cycloalkyl.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R ^w3 Is C _1-6 A haloalkyl group.

16. The compound according to any one of claims 2 to 15, or a pharmaceutically acceptable salt thereof, wherein n is 1; and/or, R ^y Is a hydrogen atom.

17. A compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt thereof, wherein

Is composed of

Is a single or double bond; m is a group of ₂ Selected from C, CR ¹³ And N; r ¹³ As defined in claim 4; preferably, the first and second electrodes are formed of a metal,

is selected from

18. The compound according to any one of claims 3 to 17, or a pharmaceutically acceptable salt thereof, wherein each R ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 An alkoxy group.

19. The compound according to any one of claims 4 to 18, or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ Is C _1-6 Alkyl or C _1-6 A haloalkyl group.

20. The compound according to any one of claims 3 to 19, or a pharmaceutically acceptable salt thereof, wherein r is 2 and L is O.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

22. a compound represented by the general formula (IV-1A):

wherein:

PG is an amino protecting group, preferably tert-butoxycarbonyl;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ^w T and r are as defined in claim 4.

23. A compound having the structure:

24. a process for preparing a compound according to claim 1, or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

X ¹ is halogen; preferably Br;

W ¹ 、W ² 、X、G ¹ 、R ¹ 、R ² 、R ⁴ to R ⁶ And R ^w As defined in claim 1.

25. A process for producing a compound represented by the general formula (IV-1) according to claim 4, or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

PG is an amino protecting group, preferably tert-butoxycarbonyl;

26. A process for producing a compound represented by the general formula (IV-2) according to claim 4 or a pharmaceutically acceptable salt thereof, which comprises:

nucleophilic substitution reaction is carried out between the compound shown in the general formula (IV-1) or the pharmaceutically acceptable salt thereof and the compound shown in the general formula (IVB) or the salt thereof to obtain the compound shown in the general formula (IV-2) or the pharmaceutically acceptable salt thereof,

wherein:

X ² is halogen; preferably iodine;

rings A, L, W ¹ 、W ² 、X、G ¹ 、R ² 、R ⁴ To R ⁶ 、R ¹³ 、R ¹⁴ 、R ^w T and r are as defined in claim 4.

27. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 21, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

28. Use of a compound of general formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 27 for the manufacture of a medicament for inhibiting SIK2 and/or SIK3.

29. Use of a compound of general formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 27 for the manufacture of a medicament for the treatment and/or prevention of a disease or disorder selected from inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving cartilage turnover injury, congenital cartilage malformations, diseases involving bone turnover injury, diseases associated with excessive secretion of TNF α, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases and diseases associated with abnormal angiogenesis; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease.

30. The use according to claim 29, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis.