CN115197208A

CN115197208A - Heteroaryl compound, preparation method and application thereof in medicine

Info

Publication number: CN115197208A
Application number: CN202210347046.5A
Authority: CN
Inventors: 杨方龙; 何卫明; 杨倩; 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: 2021-04-01
Filing date: 2022-04-01
Publication date: 2022-10-18

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

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 cell energy metabolism. Various 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 nucleus from the cytoplasm and bind to the corresponding DNA regulatory sites to exert their 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 the deacetylation of NF-kappa B proteins in inflammatory signaling pathways, thereby regulating the expression of inflammatory factors regulated by NF-kappa B.

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 multifaceted and complex mechanism of action in the immune response. After infection or tissue injury, macrophages can show a phenotype (M1 type) promoting inflammation to progress on one hand, and secrete a large amount of proinflammatory factors including TNFa and IL-12 to start the innate immunity and the secondary immune system of the body, so that the aim of eliminating microbial infection and other immunogens is fulfilled. 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. Therefore, 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.

Among the currently disclosed SIK2/SIK3 inhibitors 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 ^2a Or an N atom;

W ² is CR ^3a Or an N atom; provided that W is ¹ And W ² Not being N atoms at the same time;

X ¹ 、X ² and X ³ Are the same or different and are each independently a C atom or a N atom; provided that X is ¹ 、X ² And X ³ One of them is N atom, the other two are C atom;

R ¹ is selected from-NR ^a R ^b 、-S-R ^c 、-C(O)R ^d and-S (O) ₂ R ^e ；

R ^a And R ^b Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^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 ^a And R ^b Together with the N atom to which they are attached form a heterocyclic group optionally selected from halogen, alkyl, alkoxy, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, or a pharmaceutically acceptable salt thereof;

R ^c selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, or a pharmaceutically acceptable salt thereof;

R ^d selected from hydrogen atom, alkyl, alkenyl, alkynyl, hydroxyalkyl, heterocyclic, alkoxy, -NR ^g R ^h Aryl and heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^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; with the proviso that when X ³ Is a N atom, and X ¹ And X ² When it is a C atom, R ^d Is not an alkoxy group;

R ^e selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, -NR ^g R ^h Aryl and heteroaryl; wherein said alkaneIndependently of each other, the group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^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 ^g and R ^h Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

or R ^g And R ^h 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, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^f selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

R ^g1 and R ^h1 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

or R ^g1 And R ^h1 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, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^J selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

R ^2a 、R ^3a and R ² The same or different and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkaneOxy, cyano, hydroxyalkyl and cycloalkyl;

R ³ selected from the group consisting of hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

G ¹ is CR ⁷ Or an N atom;

R ⁴ 、R ⁶ and R ⁷ The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, alkoxy groups, alkenyl groups, alkynyl 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 halogen, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

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

R ^w is-NR ^w1 R ^w2 or-NR ^w3 -；

R ^w1 Selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl and heteroaryl; wherein said alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxySubstituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^w2 and R ^w3 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a hydroxyalkyl group, a 3-to 8-membered cycloalkyl group, a 3-to 8-membered heterocyclic group, an aryl group and a heteroaryl group; wherein said alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is ^w is-NR ^w3 When the N atom is not in contact with R ⁵ Together form a 5-to 7-membered heterocyclyl, said 5-to 7-membered heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, when R is ^w is-NR ^w3 When the N atom is not in contact with R ⁵ Together form a 5-to 7-membered heterocyclyl, said 5-to 7-membered heterocyclyl being optionally selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano and amino; more preferably, when R ^w is-NR ^w3 When the N atom is not in contact with R ⁵ Together form 5 to 7 memberedHeterocyclyl, said 5-to 7-membered heterocyclyl being optionally selected from halogen or C _1-6 Substituted by one or more substituents in the alkyl group; most preferably, when R ^w is-NR ^w3 When the N atom is not in contact with R ⁵ Together form a 6-membered heterocyclic group.

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 selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0, 1 or 2;

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

W ¹ 、W ² 、X ¹ 、X ² 、X ³ 、G ¹ 、R ¹ to R ⁴ 、R ⁶ And R ^w3 As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R is ^2a And R ^3a 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, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R ^2a And R ^3a 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 ^2a And R ^3a Are the same or different and are each independently a hydrogen atom or a halogen; most preferably, R ^2a And R ^3a Are all hydrogen atoms.

Some preferred in this disclosureIn an embodiment, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein W is ¹ Is CR ^2a ；W ² Is CR ^3a ；R ^2a And R ^3a As defined in formula (I); preferably, R ^2a And R ^3a 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, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; more preferably, R ^2a And R ^3a 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 ^2a And R ^3a Are the same or different and are each independently a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein W ¹ Is CR ^2a ；W ² Is CR ^3a (ii) a Or, W ¹ Is CR ^2a ；W ² Is N; r ^2a And R ^3a As defined in formula (I);

preferably, W ¹ Is CR ^2a ；W ² Is CR ^3a (ii) a Or, W ¹ Is CR ^2a ；W ² Is N; r is ^2a And R ^3a 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, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl;

more preferably, W ¹ Is CR ^2a ；W ² Is CR ^3a (ii) a Or, W ¹ Is CR ^2a ；W ² Is N; r is ^2a And R ^3a 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;

further preferably, W ¹ Is CR ^2a ；W ² Is CR ^3a (ii) a Or, W ¹ Is CR ^2a ；W ² Is N; r ^2a And R ^3a Are the same or different and are each independently a hydrogen atom or a halogen;

most preferably, W ¹ Is CR ^2a ；W ² Is CR ^3a (ii) a Or, W ¹ Is CR ^2a ；W ² Is N; r ^2a And R ^3a Are all hydrogen atoms.

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

Selected from:

W ² is CR ^3a Or an N atom; r is ¹ To R ³ 、R ^2a And R ^3a As defined in formula (I).

Selected from:

R ¹ to R ³ 、R ^2a And R ^3a As defined in formula (I).

Is composed of

R ¹ To R ³ 、R ^2a And R ^3a As defined in formula (I).

In some preferred embodiments of the present disclosure, the compounds of formula (I) and formula (II) or pharmaceutically acceptable salts thereof, wherein

R ¹ Is selected from-NR ^a R ^b 、-S-R ^c 、-C(O)R ^d and-S (O) ₂ R ^e ；

R ^a And R ^b 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, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, hydroxy, cyano, 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 ^a And R ^b 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 radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, 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 (a);

R ^c is C _1-6 An alkyl group; wherein said C _1-6 Alkyl is optionally selected from halogen, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, hydroxy, cyano, 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 (a);

R ^d is-NR ^g R ^h Or C _1-6 An alkoxy group; with the proviso that when X ³ Is a N atom, and X ¹ And X ² When being a C atom, R ^d Is other than C _1-6 An alkoxy group;

R ^e is selected from C _1-6 Alkyl, 3-to 8-membered cycloalkyl and-NR ^g R ^h (ii) a Wherein said C _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, hydroxy, C _1-6 Hydroxyalkyl, cyano, 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 ^g and R ^h 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, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl;

or R ^g And R ^h 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 radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano and amino;

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

R ^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 toAn 8-membered cycloalkyl group.

R ¹ Is selected from-NR ^a R ^b 、-S-R ^c and-C (O) R ^d ；

R ^a And R ^b 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 (O) R ^f Is substituted with one or more substituents of (a);

R ^c is C _1-6 An alkyl group; wherein said C _1-6 Alkyl is optionally substituted with one or more substituents selected from halogen and 3-to 8-membered heterocyclyl;

R ^d is-NR ^g R ^h ；

R ^g And R ^h Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and 3 to 8 membered cycloalkyl;

R ^f is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy and 3 to 8 membered cycloalkyl. In some preferred embodiments of the present disclosure, the compounds of formula (I) and formula (II) or pharmaceutically acceptable salts thereof, wherein

Is composed of

R ¹ Is selected from-NR ^a R ^b 、-S-R ^c 、-C(O)R ^d and-S (O) ₂ R ^e ；

or R ^a And R ^b 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 radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, 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 ^d is-NR ^g R ^h Or C _1-6 An alkoxy group;

R ^e is selected from C _1-6 Alkyl, 3-to 8-membered cycloalkyl and-NR ^g R ^h (ii) a Wherein said C _1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, hydroxy, C _1-6 Hydroxyalkyl, cyano, 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 (a);

or R ^g And R ^h 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 radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano and amino;

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

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

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^y Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano and amino; preferably, R ^y Selected from hydrogen atom, 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) or a pharmaceutically acceptable salt thereof, wherein n is 1; and/or, R ^y Selected from hydrogen atom, halogen and C _1-6 An alkyl group. In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein m is 0.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereofIn R ^w is-NR ^w1 R ^w2 ；R ^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, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, 3-to 8-membered cycloalkyl, and 3-to 8-membered heterocyclyl; 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 are each independently optionally selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, 3-to 8-membered cycloalkyl, and 3-to 8-membered heterocyclyl; 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 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) or a pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy, cyano, nitro, hydroxy, C _1-6 Hydroxyalkyl and-NR ^5a R ^5b Wherein said C _1-6 Alkyl and C _1-6 Alkoxy is independently selected from halogen and C _1-6 Alkyl radical, C _1-6 Alkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, nitro, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; r ^5a And R ^5b 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; preferably, R ⁵ Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 A hydroxyalkyl group; more preferably, R ⁵ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group; most preferably, R ⁵ is-OCHF ₂ 。

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CR ⁷ ；R ⁷ As defined in formula (I); preferably, R ⁷ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 A hydroxyalkyl group; more preferably, R ⁷ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group; further preferably, R ⁷ Is methoxy.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R is ^w3 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, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; preferably, R ^w3 Is C _1-6 Alkyl or 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 ^w3 Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more halo; most preferably, R ^w3 is-CH ₂ CF ₃ 。

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) 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 or a halogen; most preferably, R ² Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R ³ Selected from hydrogen, halogen, 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 ³ Is a hydrogen atom or C _1-6 An alkyl group; more preferably, R ³ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R is 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 radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy, C _1-6 Hydroxyalkyl, 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) or a pharmaceutically acceptable salt thereof, wherein

Is selected from

Is selected from

W ² Is CR ^3a Or an N atom; r is ^2a And R ^3a Are the same or different and are each independently a hydrogen atom or a halogen; r is ¹ Is selected from-NR ^a R ^b 、-S-R ^c and-C (O) R ^d ；R ^a And R ^b 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 (O) R ^f Is substituted with one or more substituents of (a); r ^c Is C _1-6 Alkyl, said C _1-6 Alkyl is optionally substituted with one or more substituents selected from halogen and 3-to 8-membered heterocyclyl; r ^d is-NR ^g R ^h ；R ^g And R ^h Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and 3 to 8 membered cycloalkyl; r ^f Is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy and 3 to 8 membered cycloalkyl; r ² Is a hydrogen atom; r ³ Is a hydrogen atom; r ⁴ And R ⁶ Are each a hydrogen atom; g ¹ Is CR ⁷ ；R ⁷ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group; r ^w is-NR ^w1 R ^w2 or-NR ^w3 -；R ^w1 Is a 3 to 8 membered cycloalkyl group; r is ^w2 Is a hydrogen atom; r ^w3 Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more halo; r ⁵ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group; when R is ^w is-NR ^w3 When the N atom is not in contact with R ⁵ Together form a 6-membered heterocyclic group.

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

Is selected from

W ² Is CR ^3a Or an N atom; r is ^2a And R ^3a Are the same or different and are each independently a hydrogen atom or a halogen; r ¹ Is selected from-NR ^a R ^b 、-S-R ^c and-C (O) R ^d ；R ^a And R ^b 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 (O) R ^f Is substituted with one or more substituents of (1); r is ^c Is C _1-6 Alkyl radical, said C _1-6 Alkyl is optionally substituted with one or more substituents selected from halogen and 3-to 8-membered heterocyclyl; r is ^d is-NR ^g R ^h ；R ^g And R ^h Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and 3 to 8 membered cycloalkyl; r ^f Is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy and 3 to 8 membered cycloalkyl; r ² Is a hydrogen atom; r ³ Is a hydrogen atom; r ⁴ And R ⁶ Are each a hydrogen atom; g ¹ Is CR ⁷ ；R ⁷ Is C _1-6 Alkoxy or C _1-6 A haloalkoxy group; r ^w3 Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more halo; n is 1; m is 0.

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

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 is halogen; preferably Br;

W ¹ 、W ² 、X ¹ 、X ² 、X ³ 、G ¹ 、R ¹ 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 is halogen; preferably Br;

W ¹ 、W ² 、X ¹ 、X ² 、X ³ 、G ¹ 、R ¹ to 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 (I), or a pharmaceutically acceptable salt thereof, comprising:

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

wherein:

m is

-B(OH) ₂ and-BF ₃ K；

X ^L Is halogen; preferably I;

X ¹ is a C atom, X ² Is a N atom, X ³ Is a C atom; or X ¹ Is a N atom, X ² Is a C atom, X ³ Is a C atom;

W ¹ 、W ² 、G ¹ 、R ¹ 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 of formula (II), or a pharmaceutically acceptable salt thereof, comprising:

carrying out Suzuki coupling reaction on the compound shown in the general formula (Ia) or salt thereof and the compound shown in the general formula (IIb) or salt thereof to obtain the compound shown in the general formula (II) or pharmaceutically acceptable salt thereof,

wherein:

m is

-B(OH) ₂ and-BF ₃ K；

X ^L Is halogen; preferably I;

W ¹ 、W ² 、G ¹ 、R ¹ to 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 pharmaceutical composition comprising a compound of the present disclosure represented by general formula (I), general formula (II), table a, or table B, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting SIK2 and/or SIK3.

The present disclosure further relates to the use of a compound of formula (I), formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a disease or disorder 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, 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 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 and other eczematous dermatitises, atherosclerosis and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.

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 represented by formula (I), formula (II), 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, 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, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (II) 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 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 and other eczematous dermatitises, atherosclerosis and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.

The present disclosure further relates to compounds of formula (I), formula (II) 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 general formula (I), general formula (II) 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) 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 diseases associated with abnormal angiogenesis; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease; more preferably, wherein said inflammatory 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 and other eczematous dermatitises, atherosclerosis and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.

Preferably, the disease or condition is a SIK2 and/or SIK3 mediated disease or condition.

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 dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such 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, 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 an antioxidant.

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 suspensions 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 used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and 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 employed, the severity of the disease, the age of the patient, the weight of the patient, the health condition 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, 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, 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 containing 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- ,2,2- , ,3,3- ,2,2- , </xnotran> 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, heteroaryl.

The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently 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 a carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted and when substituted the substituents are preferably one or more groups independently 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), preferably 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl), preferably 3 to 8 (e.g., 3,4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). 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 spirocycloalkyl, fused ring alkyl, 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, according to the number of spiro atoms shared between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. 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 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 ring alkyl) members, more preferably 7 to 10 (e.g. 7, 8, 9 or 10) members (i.e. 7 to 10 fused ring alkyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent 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 bicycloalkyl 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 (i.e. 6 to 14 bridged cycloalkyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 bridged cycloalkyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

said cycloalkyl ring including the rings as described aboveAlkyl (including monocycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl) is fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring(s) attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl

Tetrahydronaphthyl

Benzocycloheptalkyl and the like

Indanyl is preferred

And tetrahydronaphthyl

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, 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 one or more groups independently selected from 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 mono-or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms (i.e., a 3-to 20-membered heterocyclyl group) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), but does not include a ring portion of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms (i.e., 3 to 12 membered heterocyclyl) with 1-4 (e.g., 1,2,3 and 4) heteroatoms; more preferably 3 to 8 ring atoms (e.g., 3,4, 5, 6, 7 and 8) (i.e., 3 to 8 membered heterocyclyl), wherein 1-3 (e.g., 1,2 and 3) are heteroatoms; more preferably 3 to 6 ring atoms (i.e. 3 to 6 membered heterocyclyl), of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclyl), of which 1-3 are heteroatoms. 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 heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered spiroheterocyclyl) polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between single rings, 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), but does not include the ring portion of-O-, -O-S-or-S-, with the remaining ring atoms being carbon. It may contain one or more double bonds. 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 single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. 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 heterocyclyl groups include:

the term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members (i.e., a 5 to 20 member fused heterocyclyl group), each ring in the system sharing 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), but does not include the ring portion of-O-, -O-S-, or-S-, and the remaining ring atoms are carbon. 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 5 to 14 membered (i.e., 5 to 14 membered bridged heterocyclyl), polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which 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., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered 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 so on.

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, heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group (i.e., a 6 to 14 membered aryl group) having a conjugated pi-electron system, preferably 6 to 10 membered (e.g., 6, 7, 8, 9 or 10 membered) (i.e., 6 to 10 membered aryl), 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, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system (i.e., 5-to 14-membered heteroaryl) 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. 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 that is attached to 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, 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, heteroaryl.

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

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

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "carbonyl" refers to C = O.

In the chemical structure of the compounds described in this disclosure, a bond

Denotes an unspecified configuration, i.e. if chiral isomers are present in the chemical structure, the bond

Can be that

Or

Or at the same time comprise

And

two configurations. In the chemical structure of the compounds described in this disclosure, a bond

The configuration is not specified, i.e., either Z or E or both are contemplated.

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

when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:

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

The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only by 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-enrichment carbon (C) of (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 may be used 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 deuterated forms by reference to the relevant literatureA compound of formula (la). 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 comparable activity to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

"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 hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/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.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure which is safe and effective for use in the body of a mammal and which has the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, 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 "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 airways diseases include conditions such as COPD, asthma (e.g. intrinsic, extrinsic, dust, infantile asthma), particularly chronic or refractory asthma (e.g. late asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic Lupus Erythematosis (SLE), cutaneous lupus erythematosis, 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 and other eczematous dermatitises, inflammatory bowel diseases (e.g. crohn's disease and ulcerative colitis), atherosclerosis 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, melenib's (Mseleni) disease, and hanguddu's disease); degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

The term "diseases involving bone turnover injury" 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 syndrome, 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, colon cancer, rectal cancer, colon and rectal 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, uterine cancer, vulval cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, gastrointestinal stromal tumor (GIST), kaposi's sarcoma, and pediatric cancer.

In the context of a drug or pharmacologically active agent, the term "therapeutically effective amount" is an amount of the 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.

Synthesis of the Compounds of the disclosure

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

scheme one

The invention discloses a preparation method of a compound shown in 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 is halogen; preferably Br;

Scheme two

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

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 is halogen; preferably Br;

Scheme three

carrying out Suzuki coupling reaction on the compound shown in the general formula (Ia) or salt thereof and the compound shown in the general formula (Ib) or salt thereof under alkaline conditions and in the presence of a catalyst to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

m is

-B(OH) ₂ and-BF ₃ K；

X ^L Is halogen; preferably I;

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

Scheme four

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:

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

wherein:

m is

-B(OH) ₂ and-BF ₃ K；

X ^L Is halogen; preferably I;

Scheme five

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 alkaline conditions and in the presence of a catalyst and a ligand to obtain the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof,

wherein:

x is halogen; preferably Br;

X ¹ is a C atom, X ² Is a C atom, X ³ Is an N atom;

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

Scheme six

wherein:

x is halogen; preferably Br;

X ¹ is a C atom, X ² Is a C atom, X ³ Is an N atom;

The reagents that provide basic conditions in the above synthetic schemes include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate (potassium acetate), potassium pivalate, sodium tert-butoxide, potassium tert-butoxide, or 1, 8-diazabicycloundec-7-ene, and inorganic bases including, but 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 in scheme one and scheme two is potassium acetate; the reagent that provides basic conditions in scheme three and scheme four is cesium carbonate; the agent that provides basic conditions in scheme five and scheme six is potassium phosphate.

The catalyst used in scheme one to scheme four 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) dichloropentafendipalladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, tris (dibenzylideneacetone) dipalladium, etc., preferably [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium.

Catalysts used in scheme five and scheme six include, but are not limited to, cuprous oxide and cuprous iodide.

Ligands used in scheme five and scheme six include, but are not limited to, N ₁ ,N ₂ Di (furan-2-ylmethyl) oxyalkanamide, N1, N2-dimethylethane-1, 2-diamine, 1, 3-di (pyridin-3-yl) propane-1, 3-dione

And 1, 3-di (pyridin-2-yl) propane-1, 3-dione

The reaction of the above step is preferably carried out in a solvent including, but not limited to: 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 mixtures thereof.

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 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: agilent, MS model: 6110/6120Quadrupole 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 QOxctive)

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC1200 DAD, agilent HPLC1200VWD and Waters HPLC e2695-2489.

Chiral HPLC analytical determination Agilent 1260DAD HPLC was used.

High performance liquid preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detecor2, 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 can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoyuan ChemBiotech (Accela ChemBio Inc), darril 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 clear blue 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 without specific indication.

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

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

6- (7- (4-acetylpiperazin-1-yl) imidazo [1,2-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1

First step of

4- (imidazo [1,2-a ] pyridin-7-yl) piperazine-1-carboxylic acid tert-butyl ester 1b

The compound 7-bromoimidazo [1,2-a ] pyridine 1a (3 g,15.23mmol, nanjing Yao science Co., ltd.) was dissolved in toluene (30 mL), and 1-tert-butoxycarbonylpiperazine (4.3 g,22.82mmol, shaoyuan chemical technology (Shanghai) Co., ltd.) was added thereto, sodium tert-butoxide (2.2 g, 22.89mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (520mg, 0.90mmol), tris (dibenzylideneacetone) dipalladium (280mg, 0.31mmol), heated to 100 ℃ and stirred for 16 hours. Cooled to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography with eluent system A to give the title compound 1b (3.8 g, yield: 82.5%).

MS m/z(ESI):303.1[M+1]。

Second step of

4- (3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) imidazo [1,2-a ] pyridin-7-yl) piperazine-1-carboxylic acid tert-butyl ester 1d

Compound 1b (260mg, 0.86mmol) was dissolved in N, N-dimethylacetamide (10 mL), and the compound 6-bromo-8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1c (290mg, 0.86mmol, prepared using the method disclosed in intermediate 39 on page 162 of the specification in patent application WO2019238424A 1), potassium acetate (210mg, 2.14mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (70mg, 0.10mmol) was added, heated to 120 ℃ under nitrogen and stirred for 3 hours. Cooled to room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 1d (460 mg, yield: 95.6%). MS m/z (ESI) 560.2[ 2 ], M +1].

The third step

8-methoxy-6- (7- (piperazin-1-yl) imidazo [1,2-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1e

Compound 1d (460mg, 0.82mmol) was dissolved in a1, 4-dioxane solution of hydrogen chloride (4M, 5mL) and stirred at room temperature for 16 hours. After concentration under reduced pressure, it was dissolved in ethyl acetate (20 mL), adjusted to pH =8 with saturated sodium bicarbonate solution, the layers were separated, the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried, filtered and concentrated under reduced pressure to give the crude title product 1e (350 mg) which was used in the next step without purification.

MS m/z(ESI):460.2[M+1]。

The fourth step

Compound 1e (40mg, 0.09mmol) was dissolved in ethanol (5 mL), and triethylamine (10mg, 0.10mmol) and acetic anhydride (10mg, 0.10mmol) were added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 1 (36 mg, yield: 82.5%).

MS m/z(ESI):502.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.55(d,1H),7.75(s,1H),7.17(d,1H),7.13(d,1H),6.96(dd,1H),6.82(d,1H),4.34(q,2H),3.87(s,3H),3.61(m,6H),3.28(m,7H),2.98(t,2H)。

Example 2

8-methoxy-6- (7- (morphinylimidazo [1,2-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 2

First step of

4- (imidazo [1,2-a ] pyridin-7-yl) morpholine 2b

Compound 1a (197mg, 1.0 mmol) was dissolved in toluene (30 mL), and morpholine (174mg, 2mmol, shaoyuan chemical technology (Shanghai) Co., ltd.), sodium tert-butoxide (240mg, 1.50mmol), 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (57mg, 0.1mmol), tris (dibenzylideneacetone) dipalladium (27mg, 0.03mmol) were added, heated to 100 ℃, 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 2b (150 mg, yield: 73.8%).

MS m/z(ESI):204.2[M+1]。

Second step of

Compound 2b (50mg, 0.25mmol) was dissolved in N, N-dimethylacetamide (5 mL), compound 1c (83mg, 0.25mmol), potassium acetate (61mg, 0.63mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (36mg, 0.05mmol) were added and heated to 120 ℃ under nitrogen and stirred for 3 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system A to give the title compound 2 (69 mg, yield: 61%).

MS m/z(ESI):461.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.55(s,1H),7.74(s,1H),7.14(d,2H),6.93(d,1H),6.81(s,1H),4.34(q,2H),3.87(s,3H),3.76(t,4H),3.62(t,2H),3.24(t,4H),2.97(t,2H)。

Example 3

3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -N-methylimidazo [1,2-a ] pyridine-7-carboxamide 3

First step of

Imidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester 3a

Compound 1a (3.g, 15.22mmol, tokyo pharma technologies ltd) was dissolved in 40mL of a mixed solution of n, n-dimethylformamide and methanol (V/V =3 1), triethylamine (4.6 g, 45.65mmol), palladium acetate (684mg, 3.04mmol), 1' -bis (diphenylphosphino) ferrocene (3.4 g, 6.08mmol) were added, carbon monoxide gas was introduced three times, air was purged, heated to 100 ℃, and stirred for 16 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography using eluent system A to give the title compound 3a (1.8 g, yield: 67.1%). MS m/z (ESI) 177.1[ deg. ] M +1].

Second step of

3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) imidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester 3b

Compound 1c (160mg, 0.47mmol) was dissolved in N, N-dimethylacetamide (5 mL), and compound 3a (83mg, 0.47mmol), anhydrous potassium carbonate (227mg, 1.64mmol), pivalic acid (48mg, 0.47mmol), [1,1' -bis (diphenylphosphine) ferrocene ] dichloropalladium (35mg, 0.048 mmol) was added and suspended in 1, 4-dioxane (10 mL), heated to 100 ℃ under nitrogen and stirred for 16 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system A to give the title compound 3b (170 mg, yield: 82.9%).

MS m/z(ESI):434.1[M+1]。

1H NMR(500MHz,DMSO-d ₆ )δ8.83(d,1H),8.25(s,1H),8.15(s,1H),7.42(d,1H),7.31(s,1H),7.25(s,1H),4.36(q,2H),3.93(s,3H),3.90(s,3H),3.65(t,2H),3.01(t,2H).

The third step

Compound 3b (23mg, 0.05mmol) was dissolved in methylamine ethanol solution (2M, 2mL) and stirred at room temperature for 4 hours. After filtration, purification by high performance liquid chromatography (column: sharpSil-T Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; gradient: 32% -90%, flow rate: 30 mL/min) afforded the title compound 3 (12 mg, yield: 52.3%).

MS m/z(ESI):433.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.80(d,1H),8.72(q,1H),8.20(s,1H),8.07(s,1H),7.42(dd,1H),7.29(s,1H),7.23(s,1H),4.36(q,2H),3.90(s,3H),3.64(t,2H),3.01(t,2H),2.84(d,3H).

Example 4

8-methoxy-6- (7- ((2-morphinylethyl) thio) imidazo [1,2-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4

First step of

1- (2-Morinolinylethyl) thiourea 4c

The compound 4- (2-chloroethyl) morpholine hydrochloride 4a (7.g, 37.62mmol, shanghai Biao national chemical Co., ltd.) and thiourea 4b (2.9g, 38.10mmol, shanghai chemical Co., ltd., china pharmaceutical group) were dispersed in ethanol (55mL, 95%), heated to 85 ℃ and stirred for 24 hours. After cooling to 40 ℃ and concentrating to 20mL, suction filtration and air drying of the filter cake, the title compound 4c (5 g, yield: 70.22%) was obtained.

MS m/z(ESI):190.1[M+1]。

Second step of

2-morphinylethyl-1-thiol 4d

Compound 4c (5g, 26.42mmol) was dissolved in ethanol (10 mL), and sodium hydroxide (2.4 g, 60.75mmol) and water (20 mL) were added, followed by heating to reflux and stirring for 3 hours. Cooled to room temperature, concentrated under reduced pressure, ethanol and water were removed, benzene (50 mL) was added, followed by washing with saturated sodium chloride (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 4d (1000 mg, yield: 24.18%).

MS m/z(ESI):148.1[M+1]。

The third step

6- (7-Fluoroimidazo [1,2-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4f

The compound 7-fluoroimidazo [1,2-a ] pyridine 4e (50mg, 0.37mmol, shanghai Biao pharmaceutical science and technology Co., ltd.) was dissolved in N, N-dimethylacetamide (10 mL), and the compound 1c (120mg, 0.36mmol), potassium acetate (90mg, 0.92mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (30mg, 0.04mmol) were added, and the mixture was heated to 120 ℃ under nitrogen atmosphere and stirred for 3 hours. Cooled to room temperature, concentrated and purified by silica gel column chromatography with eluent system B to give the title compound 4f (130 mg, yield: 93.13%).

MS m/z(ESI):394.1[M+1]。

The fourth step

Compound 4f (50mg, 0.13mmol) was dissolved in N, N-dimethylformamide (5 mL), and potassium carbonate (35mg, 0.25mmol) and compound 4d (20mg, 0.15mmol) were added. After heating to 100 ℃ and stirring for 5 minutes, cooling to room temperature and pressure-concentrating the reaction mixture, it was purified by high performance liquid chromatography (column: sharpSil-T Prep C18: 30mm,5 μm; mobile phase 1: water (containing 10mmol/L of ammonium hydrogencarbonate), mobile phase 2: acetonitrile; gradient: 32% -52%, flow rate: 30 mL/min) to obtain the title product 4 (16 mg, yield: 24.18%).

MS m/z(ESI):521.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.62(d,1H),7.87(s,1H),7.52(d,1H),7.22(s,1H),7.18(s,1H),6.92(dd,1H),4.35(dd,2H),3.89(s,3H),3.63(t,2H),3.59(t,4H),3.27(t,2H),2.99(t,2H),2.64(t,2H),2.45(brs,4H)。

Example 5

4- (7- (4- (cyclopropanecarbonyl) piperazin-1-yl) imidazo [1,2-a ] pyridin-3-yl) -N-cyclopropyl-2- (difluoromethoxy) -6-methoxybenzamide 5

First step of

4- (3- (4- (cyclopropylcarbamoyl) -3- (difluoromethoxy) -5-methoxyphenyl) imidazo [1,2-a ] pyridin-7-yl) piperazine-1-carboxylic acid tert-butyl ester 5b

Compound 1b (199mg, 0.66mmol), compound 4-bromo-N-cyclopropyl-2- (difluoromethoxy) -6-methoxybenzamide 5a (221mg, 0.66mmol, prepared using the method disclosed on page 153 of the specification in patent application WO2019238424A 1), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (96mg, 0.13mmol) and potassium acetate (161mg, 1.64mmol) were mixed and dissolved in N, N-dimethylacetamide (10 mL), and heated to 100 ℃ for 16 hours under nitrogen protection. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography using eluent system B to give the title compound 5B (180 mg, yield: 49.1%). MS m/z (ESI) 558.2[ deg. ] M +1].

Second step of

N-cyclopropyl-2- (difluoromethoxy) -6-methoxy-4- (7- (piperazin-1-yl) imidazo [1,2-a ] pyridin-3-yl) benzamide 5c

Compound 5b (180mg, 0.33mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added dropwise thereto, and the reaction was stirred at room temperature for 1 hour. Concentration under reduced pressure gave the crude title compound 5c (148 mg), which was used in the next step without purification.

MS m/z(ESI):458.2[M+1]。

The third step

Compound 5c (30mg, 0.06mmol) was dissolved in 5mL of methylene chloride, triethylamine (33mg, 0.33mmol) and cyclopropanecarbonyl chloride (7mg, 0.07mmol) were added, and the reaction was stirred at room temperature for 2 hours. Purification by high performance liquid chromatography (column: welch Xtimate C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: acetonitrile 25% -45%, flow rate: 30 mL/min) afforded the title compound 5 (12 mg, yield: 34.8%).

MS m/z(ESI):526.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.44(d,1H),8.34(d,1H),7.67(s,1H),7.38(s,0.25H),7.23(s,0.5H),7.14(d,1H),7.08(s,0.25H),6.99(s,1H),6.97(d,1H),6.83(d,1H),3.88(s,3H),3.71-3.59(m,2H),3.31-3.23(m,2H),2.59-2.51(m,4H),2.83-2.75(m,1H),2.08-2.02(m,1H),0.83-0.71(m,4H),0.71-0.65(m,2H),0.51-0.43(m,2H)。

Example 6

N-cyclopropyl-2- (difluoromethoxy) -6-methoxy-4- (7- (4-methylpiperazin-1-yl) imidazo [1,2-a ] pyridin-3-yl) benzamide 6

First step of

Compound 5c (30mg, 0.06mmol) was dissolved in 3mL of methanol, followed by addition of formaldehyde (16mg, 0.2mmol, purity: 37%), stirring at room temperature for 30 minutes, addition of sodium cyanoborohydride (6 mg, 0.1mmol), and reaction at room temperature for 1 hour with stirring. Purification by high performance liquid chromatography (column: sharpSil-T Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 13 min gradient: acetonitrile 40% -53%, flow rate: 30 mL/min) afforded the title compound 6 (20mg, 64.7%). MS m/z (ESI) 472.1[ 2 ] M +1].

¹ H NMR(500MHz,DMSO-d ₆ )δ8.40(d,1H),8.33(d,1H),7.65(s,1H),7.37(s,0.25H),7.23(s,0.5H),7.13(d,1H),7.08(s,0.25H),6.98(s,1H),6.94(dd,1H),6.78(d,1H),3.87(s,3H),3.29-3.25(m,4H),2.82-2.76(m,1H),2.49-2.45(m,4H),2.24(s,3H),0.71-0.65(m,2H),0.49-0.44(m,2H)。

Example 7

4- (7- (4- (cyclopropanecarbonyl) piperazin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) -N-cyclopropyl-2- (difluoromethoxy) -6-methoxybenzamide 7

First step of

Cyclopropyl (4- (imidazo [1,2-b ] pyridazin-7-yl) piperazin-1-yl) methanone 7b

7-chloroimidazo [1,2-b ] pyridazine 7a (80mg, 0.5mmol, shanghai Biao medicine Co., ltd.) and cyclopropyl (piperazin-1-yl) methanone hydrochloride (199mg, 1.0mmol) were dissolved in toluene (5 mL), sodium t-butoxide (150mg, 1.6 mmol), 2-biscyclohexylphosphine-2 ',6' -diisopropyloxybiphenyl (25mg, 0.05mmol), bis (dibenzylideneacetone) palladium (48mg, 0.05mmol) were added, and the mixture was heated to 100 ℃ under nitrogen protection for 10 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system A to give the title compound 7b (140 mg, yield: 99.0%).

MS m/z(ESI):272.2[M+1]。

Second step of

Compound 7b (42mg, 0.15mmol), compound 5a (78mg, 0.23mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (12mg, 0.016 mmol) and potassium acetate (38mg, 0.38mmol) were mixed and dissolved in N, N-dimethylacetamide (5 mL), and the mixture was heated to 120 ℃ under nitrogen protection for 16 hours. After cooling to room temperature, filtration was carried out, and the filtrate was purified by high performance liquid chromatography (column: welch Xtimate C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: acetonitrile 25% -45%, flow rate: 30 mL/min) to give the title compound 7 (35 mg, yield: 42.9%). MS m/z (ESI) 527.2[ 2 ], [ M +1].

¹ H NMR(500MHz,DMSO-d ₆ )δ8.84(d,1H),8.33(d,1H),8.19(s,1H),7.66(s,1H),7.63(s,1H),7.31(d,1H),7.25(s,0.25H),7.10(s,0.5H),6.95(s,0.25H),3.88(s,3H),3.72-3.60(m,2H),3.50-3.41(m,2H),2.79(tq,1H),2.58-2.49(m,4H),2.10-2.03(m,1H),0.81-0.72(m,4H),0.71-0.64(m,2H),0.49-0.44(m,2H)。

Example 8

N-cyclopropyl-2- (difluoromethoxy) -6-methoxy-4- (7- (4-methylpiperazin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) benzamide 8

First step of

7- (4-Methylpiperazin-1-yl) imidazo [1,2-b ] pyridazine 8a

Compound 7a (90mg, 0.6 mmol) and 1-methylpiperazine (117mg, 1.2mmol) were dissolved in toluene (5 mL), sodium t-butoxide (141mg, 1.5 mmol), 2-bicyclohexylphosphine-2 ',6' -diisopropoxybiphenyl (27mg, 0.06mmol), bis (dibenzylideneacetone) palladium (54mg, 0.06mmol) were added, and the mixture was heated to 100 ℃ for 10 hours under nitrogen protection. After cooling to room temperature and concentration of the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system A to give the title compound 8a (110 mg, yield: 86.4%).

MS m/z(ESI):218.2[M+1]。

Second step of

Compound 8a (40mg, 0.18mmol), compound 5a (68mg, 0.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (14mg, 0.02mmol) and potassium acetate (46mg, 0.47mmol) were mixed and dissolved in N, N-dimethylacetamide (4 mL), and the mixture was heated to 120 ℃ for 16 hours under nitrogen protection. After cooling to room temperature, filtration was carried out, and the filtrate was purified by high performance liquid chromatography (column: welch Xtimate C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 15 min gradient: acetonitrile 25% -40%, flow rate: 30 mL/min) to give the title compound 8 (40 mg, yield: 46.0%).

MS m/z(ESI):473.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.81(d,1H),8.32(d,1H),8.16(s,1H),7.64(s,1H),7.62(s,1H),7.25(d,1H),7.24(s,0.25H),7.09(s,0.5H),6.95(s,0.25H),3.87(s,3H),3.38-3.34(m,4H),2.78(tq,1H),2.49-2.46(m,4H),2.25(s,3H),0.70-0.65(m,2H),0.49-0.44(m,2H)。

Example 9

3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) -N-methylpyrazolo [1,5-a ] pyridine-6-carboxamide 9

First step of

Pyrazolo [1,5-a ] pyridine-6-carboxylic acid methyl ester 9b

6-Bromopyrazolo [1,5-a ] pyridine 9a (1g, 5.1mmol, shanghai Biao pharmaceuticals Co., ltd.) was dissolved in 16mL of a mixed solvent of N, N-dimethylformamide and methanol (V/V = 3), triethylamine (1.54g, 15.2mmol), palladium acetate (228mg, 1.0mmol) and 1,1' -bis (diphenylphosphino) ferrocene (173mg, 2.0mmol) were added, and a carbon monoxide gas was substituted, and the mixture was heated to 100 ℃ and reacted for 16 hours. After cooling to room temperature and concentration of the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system B to give the title compound 9B (310 mg, yield: 34.7%).

MS m/z(ESI):177.1[M+1]。

Second step of

N-methylpyrazolo [1,5-a ] pyridine-6-carboxamide 9c

Compound 9b (158mg, 0.9 mmol) was dissolved in 2M methylamine ethanol solution (3.6 mL,7.2 mmol), the reaction was stirred at room temperature for 4 hours, and the reaction was concentrated under reduced pressure to give crude title compound 9c (157 mg), which was used in the next step without purification.

MS m/z(ESI):176.2[M+1]。

The third step

Compound 9c (39mg, 0.22mmol), compound 1c (50mg, 0.15mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (11mg, 0.015mmol) and potassium acetate (36mg, 0.37mmol) were mixed and dissolved in N, N-dimethylacetamide (5 mL), and the mixture was heated to 120 ℃ under nitrogen protection for 16 hours. After cooling to room temperature, it was filtered, and the filtrate was purified by high performance liquid chromatography (column: sharpSil-T Prep C18: 30mm,5 μm; mobile phase 1: water (containing 10mmol/L of ammonium bicarbonate), mobile phase 2: acetonitrile; 12 min gradient: acetonitrile 27% -39%, flow rate: 30 mL/min) to give the title compound 9 (20 mg, yield: 31.3%).

MS m/z(ESI):433.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.23(d,1H),8.71-8.64(m,2H),8.16(d,1H),7.78(dd,1H),7.30-7.22(m,2H),4.34(q,2H),3.91(s,3H),3.62(t,2H),3.00(t,2H),2.84(d,3H)。

Example 10

8-methoxy-6- (6- (4-methylpiperazin-1-yl) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 10

First step of

6- (4-Methylpiperazin-1-yl) pyrazolo [1,5-a ] pyridine 10a

Compound 9a (228mg, 1.2mmol) and 1-methylpiperazine (170mg, 1.7mmol) were dissolved in toluene (10 mL), sodium tert-butoxide (170mg, 1.7mmol) was added,4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene(40mg, 0.07mmol), bis (dibenzylideneacetone) palladium (20mg, 0.02mmol), and heating to 100 ℃ under the protection of nitrogen for 16 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system A to give the title compound 10a (90 mg, yield: 36.0%).

MS m/z(ESI):217.2[M+1]。

Second step of

3-iodo-6- (4-methylpiperazin-1-yl) pyrazolo [1,5-a ] pyridine 10b

Compound 10a (90mg, 0.4 mmol) was dissolved in acetonitrile (5 mL), N-iodosuccinimide (95mg, 0.4 mmol) was added under ice-bath conditions, and the reaction was stirred for 1 hour while maintaining ice-bath conditions. The reaction was quenched with water (20 mL), extracted with ethyl acetate (40 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 10B (130 mg, yield: 91.3%). MS m/z (ESI) 343.1[ 2 ] M + 1.

The third step

Compound 10b (50mg, 0.15mmol) and compound 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 10c (65mg, 0.17mmol, prepared using the method disclosed on page 70 of the description in patent application WO2020239660 A1) were dissolved in a mixed solvent of 12mL 1,4-dioxane and water (V/V = 1), cesium carbonate (150mg, 0.46mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (10mg, 0.01mmol) were added, nitrogen protected, and the mixture was heated to 90 ℃ for 16 hours. Cooled to room temperature and purified by high performance liquid chromatography (column: welch XTimate C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: acetonitrile 30% -50%, flow rate: 30 mL/min) to give the title compound 10 (34 mg, yield: 49.1%).

MS m/z(ESI):474.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.38(s,1H),8.15(s,1H),7.97(d,1H),7.41(dd,1H),7.20(s,1H),7.18(s,1H),4.33(q,2H),3.89(s,3H),3.61(t,2H),3.18-3.09(m,4H),2.98(t,2H),2.50-2.45(s,4H),2.25(s,3H)。

Example 11

4- (6- (4- (cyclopropanecarbonyl) piperazin-1-yl) pyrazolo [1,5-a ] pyridin-3-yl) -N-cyclopropyl-2- (difluoromethoxy) -6-methoxybenzamide 11

First step of

6-bromo-3-iodopyrazolo [1,5-a ] pyridine 11a

Compound 9a (8g, 40.6 mmol) was dissolved in acetonitrile (200 mL), and N-iodosuccinimide (9.13g, 40.6 mmol) was added under ice-bath conditions, and the reaction was stirred for 1 hour while maintaining ice-bath conditions. Most of the solvent was removed by concentration under reduced pressure, the reaction was quenched with water (50 mL), extracted with ethyl acetate (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title product 11a (9.6 g, yield: 73.2%).

MS m/z(ESI):322.8[M+1]。

Second step of

4- (6-Bromopyrazolo [1,5-a ] pyridin-3-yl) -N-cyclopropyl-2- (difluoromethoxy) -6-methoxybenzamide 11c

Compound 11a (2.9g, 9.0mmol) and compound N-cyclopropyl-2- (difluoromethoxy) -6-methoxy-4- (4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide 11b (3.43g, 9.0mmol, prepared using the method disclosed in patent application WO2019238424A1, page 178) were dissolved in 150mL of a mixed solvent of 1, 4-dioxane and water (V/V = 5). After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title product 11c (1.8 g, yield: 44.5%).

MS m/z(ESI):452.0[M+1]。

The third step

Compound 11c (32mg, 0.07mmol) and cyclopropyl (piperazin-1-yl) methanone (22mg, 0.14mmol) were dissolved in 1, 4-dioxane (5 mL), sodium tert-butoxide (20mg, 0.21mmol) and methanesulfonic acid (2-dicyclohexylphosphine-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (13mg, 0.014mmol) were added, and the mixture was heated to 110 ℃ under nitrogen for 16 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, the filtrate was filtered and purified by high performance liquid chromatography (column: welch XTimate C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: acetonitrile 30% -50%, flow rate: 30 mL/min) to give the title compound 11 (5 mg, yield: 13.4%).

MS m/z(ESI):526.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.34(s,1H),8.28(d,1H),8.21(s,1H),7.89(d,1H),7.48-7.42(m,1H),7.37(s,0.25H),7.22(s,0.5H),7.15(s,1H),7.07(s,0.25H),7.00(s,1H),3.89(s,3H),3.72-3.61(m,2H),3.20-3.06(m,2H),2.82-2.73(m,1H),2.65-2.52(m,4H),2.09-2.03(m,1H),0.81-0.71(m,4H),0.70-0.64(m,2H),0.52-0.43(m,2H)。

Example 12

4- (6- (4- (cyclopropanecarbonyl) piperazin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -N-cyclopropyl-2- (difluoromethoxy) -6-methoxybenzamide 12

First step of

Cyclopropyl (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) piperazin-1-yl) methanone 12b

6-bromopyrazolo [1,5-a ] pyrimidine 12a (1g, 5.05mmol) and cyclopropyl (piperazin-1-yl) methanone (1.2g, 6.3mmol) were dissolved in toluene (40 mL), sodium tert-butoxide (1.56g, 16.2mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (423mg, 0.5 mmol) were added, and the mixture was heated to 100 ℃ under nitrogen protection for 16 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system A to give the title compound 12b (50 mg, yield: 3.6%). MS m/z (ESI) 272.2[ 2 ], [ M +1].

Second step of

Cyclopropyl (4- (3-iodopyrazolo [1,5-a ] pyrimidin-6-yl) piperazin-1-yl) methanone 12c

Compound 12b (50mg, 0.18mmol) was dissolved in acetonitrile (2 mL), and N-iodosuccinimide (42mg, 0.18mmol) was added under ice-cooling, and the reaction was stirred for 1 hour while maintaining ice-cooling conditions. Concentrate under reduced pressure to remove most of the solvent, dilute with water (5 mL), extract with ethyl acetate (10 mL. Times.3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the crude title compound 12c (65 mg) which was used in the next step without purification. MS m/z (ESI) 398.2[ 2 ] M +1].

The third step

Compound 12c (65mg, 0.16mmol) and compound N-cyclopropyl-2- (difluoromethoxy) -6-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide 11b (76mg, 0.2mmol) were dissolved in 6ml of a mixed solvent of 1, 4-dioxane and water (V/V = 5), cesium carbonate (160mg, 0.49mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (13mg, 0.02mmol) was added, nitrogen protected, and the temperature was raised to 90 ℃ for 2 hours. Cooled to room temperature, concentrated under reduced pressure and purified by high performance liquid chromatography (column: welch Xtimate C18150 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 15 min gradient: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title product 12 (40 mg, yield: 46.4%).

MS m/z(ESI):527.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.78(d,1H),8.51(s,1H),8.42(d,1H),7.72(d,1H),7.61(s,1H),7.00(s,0.25H),6.86(s,0.5H),6.71(s,0.25H),4.06-3.99(m,2H),3.96(s,3H),3.88-3.80(m,2H),3.31-3.28(m,2H),3.25-3.19(m,2H),2.90-2.82(m,1H),2.09-2.01(m,1H),0.98-0.92(m,2H),0.91-0.85(m,2H),0.84-0.78(m,2H),0.66-0.60(m,2H)。

Example 13

N-cyclopropyl-2- (difluoromethoxy) -6-methoxy-4- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-1-yl) benzamide 13

First step of

5- (4-Methylpiperazin-1-yl) -1H-benzo [ d ] imidazole 13b

5-bromo-1H-benzo [ d ] imidazole 13a (3 g,15.2mmol, shanghai medicine Co., ltd.) and 1-methylpiperazine (1.83g, 18.3 mmol) were dissolved in 1M lithium hexamethyldisilazide tetrahydrofuran solution (22.8mL, 22.8 mmol), and 2-dicyclohexylphosphino-2 ',6' -diisopropoxy-biphenyl (213mg, 0.5 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (383mg, 0.5 mmol) were added and the mixture was heated to 70 ℃ under nitrogen protection to react for 10 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography with eluent system A to obtain the title compound 13b (1.6 g, yield: 48.6%).

MS m/z(ESI):217.2[M+1]。

Second step of

Compound 13b (60mg, 0.3mmol) and compound 5a (94mg, 0.3mmol) were dissolved in dimethyl sulfoxide (3 mL), and cuprous oxide (8mg, 0.06mmol), N, was added ₁ ,N ₂ Bis (furan-2-ylmethyl) oxyalkamide (14mg, 0.06mmol) and potassium phosphate (118mg, 0.6 mmol), under nitrogen protection, and heating to 120 ℃ for 20 hours. Cooled to room temperature, filtered and the filtrate purified by high performance liquid chromatography (column: welch XTimate C18150 × 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient: acetonitrile 31% -42%, flow rate: 30 mL/min) to give the title product 13 (24 mg, yield: 18.3%).

MS m/z(ESI):472.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.53(s,1H),8.41(d,1H),7.57(d,1H),7.42(s,0.25H),7.27(s,0.5H),7.26-7.23(m,2H),7.12(s,0.25H),7.15-7.09(m,2H),3.90(s,3H),3.19-3.12(m,4H),2.84-2.77(m,1H),2.50-2.44(m,4H),2.24(s,3H),0.72-0.66(m,2H),0.50-0.45(m,2H)。

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 microfluid chip, and allowing an AMARA substrate and a product to enter a capillary with an electric field to 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, which is a concentration 50 times the highest concentration point of the compound in the reaction system, with 100% DMSO to dilute the compound at this concentration 4 times, with 9 concentration points, 10 concentration points in total, 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; mu.L of 5 Xconcentration compound was taken in the reaction wells, and 5. Mu.L of 10% DMSO was added to the negative control wells (no enzyme added) and the positive control wells (no compound added with enzyme). 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. Diluting AMARA and ATP to 2.5-fold concentration (AMARA reaction final concentration of 3. Mu.M, ATP reaction final concentration of 128. Mu.M) in 1 Xkinase buffer, transferring 10. Mu.L of substrate and ATP solution to the reaction system, mixingAfter the completion of the reaction at 28 ℃ for 60 minutes, 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	>2000	37
2	1962	50
			3	1006	66
4	>2000	41
			7	385	95
8	238	93
			9	437	95
11	237	93
			12	229	99
13	1361	97

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, M1028-100 ML)

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 the substrate AMARA 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 the ADP generation reaction is completed, adding ADP-Glo reagent to terminate the reaction and consume the rest 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. After 5. Mu.L of the reaction was mixed well, the mixture was incubated at room temperature for 120 minutes. The reaction was stopped by adding 5. Mu.L ADP-Glo reagent and incubated at room temperature for 40min to deplete the remaining ATP. Then 10. Mu.L of kinase assay reagent was added and incubated at room temperature for 30min. Rear readingThe obtained value is calculated as the inhibition rate according to the following formula: inhibition =100-100 × (test well value-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 compounds of the disclosure ₅₀ Value of

Example numbering	IC ₅₀ (nM)	Imax(％)
			1	20	101
2	34	100
			3	16	98
4	47	101
			5	7	101
6	6	102
			7	13	98
8	9	99
			9	14	100
10	29	100
			11	14	98
12	8	101
			13	30	99

And (4) conclusion: the disclosed compound has a good inhibitory effect on SIK2, and the selective inhibitory effect on SIK2 can be obtained by comparing test example 1 with test example 2.

Test example 3 inhibition of human SIK3 kinase by Compounds of the disclosure

1. Experimental materials and instruments

SIK3 enzyme (Promega, VA 7300)

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

3.DMSO(Sigma,D2650)

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

Tris PH7.5 2M (Biyuntian, B548139-0500)

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

7.EGTA(Sigma,E3889-100G)

DTT 2M (Biotechnology, B645939)

9. 96-well plate(Corning,3795)

10. 384-well 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)

2. Experimental procedure

SIK3 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 SIK3. 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 simultaneously converting 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 the 100X concentration of the highest concentration point of the compound in the reaction system, diluting the compound at this concentration by 4 times by 10 concentration points of 100% DMSO, and blank wells by 100% DMSO. The serially diluted compounds and 100% DMSO were further diluted 20-fold in water to 5 Xconcentration and mixed well; 1 μ L of 5 Xconcentration compound was placed in reaction wells, negative control wells (no enzyme added)) And positive control wells (enzyme-free compound added) 1 μ L of 5% dmso was added. SIK3 enzyme and AMARA were diluted in Reaction buffer (25mM Tris, pH7.5, 0.01% Triton X-100,0.5mM EGTA,5mM magnesium chloride, 2.5mM DTT) to 2.5 Xconcentration (final Reaction concentration SIK3:10nM AMARA. ATP was diluted in Reaction buffer to 2.5 Xconcentration (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 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. After reading, the resulting value was calculated as the inhibition according to the following formula: inhibition =100-100 × (test well value-negative control value)/(positive control value-negative control value). The inhibition curve is drawn according to each concentration of the compound and the corresponding inhibition rate by Graphpad Prism software, and the concentration of the compound when the inhibition rate reaches 50 percent, namely IC is calculated ₅₀ The value is obtained.

TABLE 3 IC of enzymatic inhibition of human SIK3 by the compounds of the present disclosure ₅₀ Value of

Example numbering	IC ₅₀ (nM)	Imax(％)
			6	9	93
9	15	96
			11	4	96
12	3	90

And (4) conclusion: the disclosed compound has a good inhibitory effect on SIK3, and the selective inhibitory effect on SIK3 of the disclosed compound can be obtained by comparing test example 1 with test example 3.

Test example 4 inhibitory Activity of the Compound of the present invention on TNF α secretion from human monocytes stimulated with LPS

1. Experimental materials and instruments

1. Magnetic bead for separating human CD14 monocyte (Meitian and whirlwind, 130-050-201)

2. Human TNF-alpha enzyme-linked immune reaction kit (Xinbo Sheng, EHC103a.96.10)

3.DMSO(Sigma,D2650)

4. Human peripheral mononuclear cells (Miaoshun biology, PB 250F)

5.RPMI-1640(GE Healthcare,SH30809.01)

6. Fetal bovine serum (Gibco, 10099-141)

7. Phosphate Buffered Saline (PBS) PH7.4 (Yuanpeiye, B320)

8. Bovine Serum Albumin (BSA) (MP Biomedicals, 9048-46-8)

9.EDTA(0.5M),pH 8.0(Life technology,AM9260G)

10. Lipopolysaccharide (LPS) (Sigma, L2880)

11.96 hole round bottom board (Corning, 3788)

LS magnetic column (beautiful whirlwind, 130-042-401)

13. Carbon dioxide incubator (Thermo scientific, i 160)

14.15 ml centrifuge tube (Corning)

15. Biological safety cabinet (Shanghai Li Shen scientific instruments Co., ltd., HFsafe-1200 LC)

16. High speed refrigerated centrifuge (Thermo scientific, ST 40R)

17. Plate washing machine (Bio Tek Instruments,405 TSU)

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

PHERAstar FS microplate reader (BMG Labtech)

2. Experimental procedure

Human peripheral blood mononuclear cells secrete a variety of cytokines upon stimulation by pathogens such as lipopolysaccharides. Among these factors are pro-inflammatory cytokines (e.g., TNF. Alpha., IL-6, IL-. Beta., etc.) that promote inflammatory responses, and cytokines that inhibit inflammatory responses or act as immunomodulating agents. In the experiment, the content of TNF alpha in a culture medium for culturing human peripheral blood mononuclear cells is detected by an Elisa method, and the inhibition or promotion effect of the compound on the release of the cytokines is evaluated.

Human peripheral blood mononuclear cells were cultured in RPMI1640 medium (hereinafter referred to as complete medium) containing 10% fetal bovine serum. The CD14+ monocyte isolation buffer was a PBS solution containing 0.5% BSA and 2mM EDTA. The LPS powder was dissolved in sterile water to 1mg/mL and stored in a refrigerator at-20 ℃ in portions.

Monocyte isolation and LPS treatment: centrifuging the PBMC at 300g at 4 ℃ for 10min, carefully sucking out supernatant, resuspending cells with a proper volume of precooled cell separation buffer solution, counting, adjusting the cell concentration to 10^7 per 80 mu L of separation buffer solution, fully and gently blowing the cells uniformly, adding CD14+ cell sorting magnetic beads according to the proportion of 20 mu L of magnetic beads per 10^7 cells, fully and uniformly mixing, putting the mixture in a refrigerator at 4 ℃ for incubation for 15 min, and shaking the mixture uniformly for several times. Adding precooling buffer solution in a ratio of 2mL of buffer solution per 10^7 cells, reversing, mixing evenly, then 300g, and centrifuging for 10min at 4 ℃. And (3) placing the LS cell collection column on a magnetic frame while waiting for centrifugation, placing a waste liquid collection tube below the LS cell collection column, and adding 3mL of precooling buffer solution to rinse the LS column. Resuspend the cell pellet at a ratio of 0.5-1mL buffer per 10^8 cells, and add to the LS column. When the magnetic beads bound to the cells flow through the LS column, they are attracted by the magnetic force, and the cells not bound to the magnetic beads flow away from the column. The LS column was rinsed three times with 3mL of pre-chilled buffer. And replacing the cell collecting pipe, placing the cell collecting pipe under the LS column, adding 5mL of culture medium into the LS column, taking the LS column off the magnetic frame, installing a piston to stably and uniformly push the cells out of the LS column, and collecting the cells into the cell collecting pipe. The collected cells were counted and diluted to 6.25X 10^6/mL with complete medium, 160. Mu.L of cell suspension was added per well in a 96 round bottom plate so that the total number of seeded cells per well was 1X 10^5, and the cells were transferred to an incubator for 4 hours.

The 20mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 5mM, which is a 500X concentration of the highest concentration point of the compound in the reaction system, and the compound at this concentration was diluted 4-fold with 100% DMSO to 9 concentration points, and the blank well was 100% DMSO. The serially diluted compounds and 100% dmso were further diluted 50-fold in complete medium to 10 × concentration and mixed well; 20 μ L of 5 Xconcentration of compound was taken in cell culture wells, and 20 μ L of 2% DMSO was added to negative control wells (without LPS) and positive control wells (without LPS). LPS stock (1 mg/mL) was diluted 500-fold to 2. Mu.g/mL with complete medium, 20. Mu.L of LPS solution was added to each well to give a final concentration of 200ng/mL of LPS, and shaken well by hand. Placing the cells back at 37 ℃,5% CO ₂ The culture was carried out in an incubator, and after 20 hours, the supernatant was collected and subjected to Elisa test.

ELISA detection of TNF α secretion levels: detection of cytokines in cell culture media was performed according to the Elisa kit instructions. Using standards&The specimen universal diluent dissolves the standard and is diluted to the following concentrations as a standard curve: 1000. 500, 250, 125, 62.5, 15.6, 0pg/mL. Using a standard sample&Diluting the specimen by proper times with universal diluent, and adding standard substance into blank holes&The general diluent of the specimen, the specimen or standard substances (100 mu L/hole) with different concentrations are added into the other corresponding holes, the reaction holes are sealed by sealing plate gummed paper, and the reaction holes are incubated for 90 minutes in a constant temperature box at 37 ℃ in a dark place. The 30 × concentrated biotinylated antibody was diluted to 1 × working solution with biotinylated antibody diluent 20 minutes prior to use. The plate was washed 5 times with a plate washer at 300. Mu.L/well. Biotinylated antibody working solution (100. Mu.L/well) was added to each well. The reaction wells were sealed with a new sealing plate of gummed paper, incubated at 37 ℃ in a thermostat for 60 minutes in the dark. The 30 Xconcentrated enzyme conjugate was diluted to 1 Xworking solution with enzyme conjugate diluent 20 minutes prior to use. The plate was washed 5 times with a plate washer at 300. Mu.L/well. Adding enzyme conjugate per wellWorking solution (100. Mu.L/well). The reaction wells were sealed with a new sealing plate of gummed paper, incubated at 37 ℃ in a thermostat, protected from light for 30 minutes. The plate was washed 5 times with a plate washer at 300. Mu.L/well, the plate was dried, 100. Mu.L/well of a chromogenic substrate (TMB) was added, and incubated at 37 ℃ in a thermostat for 15 minutes in the absence of light. Add 100. Mu.L/well of the reaction stop solution, mix well and measure OD450 value within 3 minutes. The TNF α concentration per well, obtained from the standard curve, was calculated as the inhibition according to the following formula: inhibition =100-100 × (test well value-negative control value)/(positive control value-negative control value). The inhibition curve is drawn according to each concentration of the compound and the corresponding inhibition rate by Graphpad Prism software, and the concentration of the compound when the inhibition rate reaches 50 percent, namely IC is calculated ₅₀ The value is obtained.

TABLE 4 inhibition of TNF α secretion by LPS-stimulated human monocytes by the compounds of the disclosure IC ₅₀ Value of

Example numbering	IC ₅₀ (nM)	Imax(％)
			5	14	99
6	20	100
			7	69	99
8	53	96
			11	28	100

And (4) conclusion: the disclosed compound has good inhibition effect on TNF alpha secretion of human monocytes stimulated by LPS.

Test example 5 pharmacokinetic evaluation

1. SD rat test

1. Abstract

The drug concentration in plasma of SD rats at various times after gavage (i.g.)/intravenous injection (i.v.) administration of the compound of example 12 was measured by LC/MS method using SD rats as test animals. The pharmacokinetic behavior of the compounds of the disclosure in SD rats was studied and their pharmacokinetic profile was evaluated.

2. Test protocol

2.1 test drugs

The compound of example 12.

2.2 test animals

The SD rats are divided into 2 groups on average with 8 male and female halves, and are provided by Zhejiang Weitonglihua laboratory animal technology GmbH. After fasting overnight, the administration was by gavage and intravenous injection, respectively.

2.3 pharmaceutical formulation

A certain amount of the compound of example 12 was weighed, 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).

2.4 administration of drugs

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

Intravenous administration group: the dose was 1.0mg/kg and the volume was 5.0mL/kg.

3. Operation of

The 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 2 minutes (4 ℃), plasma was separated within 1 hour, and the blood was stored with dry ice for measurement. The blood collection to centrifugation process is operated under ice bath condition. Food was consumed 2 hours after dosing.

Intravenous administration group: blood was collected before administration and 5 minutes, 30 minutes, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, and the group administered with intragastric administration was treated.

Determination of the content of the test compounds in the plasma of SD rats after administration of the drugs at different concentrations: SD rat plasma samples were taken at 50. Mu.L each time post-dose, 25. Mu.L of tolbutamide (2 ug/mL) was added to each sample, and the protein was precipitated with 450. Mu.L of acetonitrile, vortexed, and centrifuged at 3700rpm for 10 minutes. 0.5. Mu.L of the supernatant was analyzed by LC/MS/MS.

4. Pharmacokinetic parameter results

TABLE 5 pharmacokinetic parameters of the compounds of this disclosure in SD rats

And (4) conclusion: the compound disclosed by the invention has good drug absorption activity in an SD rat body and pharmacokinetic advantage.

2. Beagle dog test

1. Abstract (abstract)

The drug concentration in plasma of beagle dogs at various times after gavage (i.g.) and intravenous (i.v.) administration of the compound of example 12 was measured by LC/MS method using beagle dogs as test animals. The pharmacokinetic behavior of the compounds of the disclosure in beagle dogs was studied and their pharmacokinetic profile was evaluated.

2. Test protocol

2.1 test drugs

The compound of example 12.

2.2 test animals

The beagle dogs were 8 dogs, half male and female, and were divided into 2 groups on average, and were provided by Shanghai Medity biomedical corporation. After fasting overnight, the administration was by gavage and intravenous injection, respectively.

2.3 pharmaceutical formulation

A certain amount of the compound of example 12 was weighed, and 5% by volume of DMSO +30% by volume of PG +30% by volume of PEG400+35% by volume of physiological saline were added to prepare a clear solution (gavage group) of 0.4mg/mL and a clear solution (intravenous group) of 0.25 mg/mL.

2.4 administration of drugs

And (3) intragastric administration group: the dose was 2.0mg/kg and the volume was 5.0mL/kg.

Intravenous administration group: the dose was 0.5mg/kg and the volume was 2.0mL/kg.

3. Operation of

The intragastric administration group: 0.5mL of blood was collected from the forelimb vein at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours before and after administration, and the blood was centrifuged at 10000rpm for 2 minutes (4 ℃) in an EDTA-K2 anticoagulation tube, and plasma was separated at 1 hour, and stored in a refrigerator/dry ice at-80 ℃ for testing. The blood collection to centrifugation process is operated under ice bath condition. Food was consumed 3 hours after dosing.

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

Determining the content of the test compound in the plasma of beagle dogs after administration of drugs with different concentrations: 50 μ L of beagle plasma samples were taken at various time points post-dose, each sample was precipitated with 450 μ L acetonitrile to precipitate the protein, 25 μ L camptothecin (1 ug/mL) as an internal standard solution was added, the mixture was vortexed for 1 minute, and centrifuged at 3700rpm for 10 minutes. 0.5. Mu.L of the supernatant was analyzed by LC/MS/MS.

4. Pharmacokinetic parameter results

Table 6 pharmacokinetic parameters of the compounds of the present disclosure in beagle dogs

And (4) conclusion: the compound disclosed by the invention has good drug absorption activity in a beagle body, is high in oral bioavailability and has pharmacokinetic advantages.

Claims

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

wherein:

W ¹ is CR ^2a Or an N atom;

X ¹ 、X ² and X ³ Are the same or different and are each independently a C atom or a N atom; with the proviso that X ¹ 、X ² And X ³ One of them is N atom, the other two are C atom;

R ¹ is selected from-NR ^a R ^b 、-S-R ^c 、-C(O)R ^d and-S (O) ₂ R ^e ；

R ^a And R ^b Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, or a pharmaceutically acceptable salt thereof;

R ^c selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^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 ^d selected from hydrogen atom, alkyl, alkenyl, alkynyl, hydroxyalkyl, heterocyclic, alkoxy, -NR ^g R ^h Aryl and heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^f 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^J 、-S(O) ₂ NR ^g1 R ^h1 Aryl and heteroaryl, or a pharmaceutically acceptable salt thereof; with the proviso that when X ³ Is a N atom, and X ¹ And X ² When it is a C atom, R ^d Is not an alkoxy group;

R ^e selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, -NR ^g R ^h Aryl and heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, -C (O) R ^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 ^f selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclic groups;

R ^g1 and R ^h1 The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

R ^2a 、R ^3a and R ² The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxyalkyl, and cycloalkyl;

R ³ selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

G ¹ is CR ⁷ Or an N atom;

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

R ^w is-NR ^w1 R ^w2 or-NR ^w3 -；

R ^w1 Selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl and heteroaryl; wherein said alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^w2 and R ^w3 The same or different and each is independently selected from hydrogen atom, alkyl, halogenated alkyl, alkenyl, alkynyl, hydroxylAlkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl and heteroaryl; wherein said alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof 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 ¹ 、X ² 、X ³ 、G ¹ 、R ¹ to R ⁴ 、R ⁶ And R ^w3 As defined in claim 1.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein W ¹ Is CR ^2a ；W ² Is CR ^3a (ii) a Or, W ¹ Is CR ^2a ；W ² Is N; r is ^2a And R ^3a As defined in claim 1;

preferably, W ¹ Is CR ^2a ；W ² Is CR ^3a (ii) a Or, W ¹ Is CR ^2a ；W ² Is N; r is ^2a And R ^3a 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.

4. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein

Selected from:

W ² is CR ^3a Or an N atom; r ¹ To R ³ 、R ^2a And R ^3a As defined in claim 1.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ¹ Is selected from-NR ^a R ^b 、-S-R ^c 、-C(O)R ^d and-S (O) ₂ R ^e ；

or R ^a And R ^b 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 radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, 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 ^c is C _1-6 An alkyl group; wherein said C _1-6 Alkyl is optionally selected from halogen, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, hydroxy, cyano, 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 ^g and R ^h 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, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heteroA cyclic group;

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

6. The compound of the general formula (I) according to any one of claims 2 to 5, wherein n is 1; and/or, R ^y Selected from hydrogen atom, halogen and C _1-6 An alkyl group.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 5, wherein R ^w is-NR ^w1 R ^w2 ；R ^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, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; 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, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1,3 to 5 and 7, wherein R ⁵ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 A hydroxyalkyl group.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein G ¹ Is CR ⁷ ；R ⁷ As defined in claim 1; preferably, R ⁷ Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 A hydroxyalkyl group.

10. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ^w3 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, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ² Selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

12. The compound of the general formula (I) according to any one of claims 1 to 11A compound or a pharmaceutically acceptable salt thereof, wherein R ³ Is a hydrogen atom or C _1-6 An alkyl group.

13. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, wherein 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.

14. A compound of general formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

15. a compound or salt thereof selected from the group consisting of:

16. a process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

x is halogen; preferably Br;

W ¹ 、W ² 、X ¹ 、X ² 、X ³ 、G ¹ 、R ¹ to R ⁶ And R ^w As defined in claim 1.

17. 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 14, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 for the manufacture of a medicament for inhibiting SIK2 and/or SIK3.

19. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 for the preparation 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 disorder is an inflammatory disease or an autoimmune disease.

20. The use according to claim 19, 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 and other eczematous dermatitis, atherosclerosis and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.