Heteroaryl compounds, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to heteroaryl compounds, processes for their preparation and their use in medicine. In particular, the present disclosure relates to a heteroaryl compound of general formula (I), processes for its preparation, pharmaceutical compositions containing the compound and its use as a therapeutic agent, in particular as a SIK inhibitor and in the manufacture of a medicament for the treatment and / or prevention of an inflammatory or autoimmune disease. Wherein the groups in general formula (I) are as defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a heteroaryl compound, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to heteroaryl compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as SIK inhibitors in the preparation of medicaments for the treatment and / or prevention of inflammatory or autoimmune diseases. Background Technology

[0002] Salt-inducible kinases (SIKs), including SIK1, SIK2, and SIK3, belong to the AMP-dependent protein kinase (AMPK) family. These serine / threonine kinases play a crucial role in the regulation of cellular energy metabolism. Various extracellular signals, including hormones and chemokines, can activate corresponding G protein-coupled receptor / cAMP signaling pathways, further activating protein kinase A (PKA), protein kinase C (PKC), and calcium-calmodulin-dependent protein kinase (CaMK) signaling networks, regulating various functions such as glucose metabolism, lipid metabolism, energy metabolism, and cell differentiation. SIK kinases are downstream of protein kinase A (PKA). PKA directly phosphorylates SIK kinases, increasing their binding to 14-3-3 regulatory proteins, thereby releasing and activating downstream SIK substrates, mainly including two types of transcription factors: CREB-regulated transcription activators (CRTCs) and histone deacetylases (HDAC4, 5, 7, and 9). Released CRTCs and HDACs enter the nucleus from the cytoplasm, bind to corresponding DNA regulatory sites, and exert their transcriptional regulatory functions. Downstream genes mainly include Pck1 and G6PC, which regulate metabolism, and Ptgs2, IL-10, TTP, etc., which are involved in the inflammatory response. In addition, HDACs also participate in the deacetylation of NF-κB protein in the inflammatory signaling pathway, thereby regulating the expression of NF-κB-regulated inflammatory factors.

[0003] Recent studies have shown that SIK kinases play a crucial role in the immune response of innate immune cells, particularly macrophages and dendritic cells. Innate immune cells have a complex and multifaceted mechanism of action in the immune response. Following infection or tissue damage, macrophages exhibit a phenotype that promotes inflammation (M1 type), secreting large amounts of pro-inflammatory factors, including TNFα and IL-12, to activate the body's innate and secondary immune systems and clear microbial infections and other immunogens. On the other hand, macrophages also play a role in immune regulation, differentiating into immunomodulatory macrophages (M2 type), secreting inflammatory suppressor factors such as IL-10 and IL-1α to ensure the control and timely elimination of inflammation. Pro-inflammatory M1 macrophages are closely associated with autoimmune diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. M2 macrophages, which regulate the inflammatory response, can effectively suppress the development of inflammation. Furthermore, IL-10 knockout mice exhibit a phenotype associated with inflammatory bowel disease, and IL-10 gene deficiency is associated with the occurrence of inflammatory bowel disease in humans. SIK kinases inhibit IL-10 expression by regulating CREB transcription factor and promote TNFα expression by regulating HDAC and NFkB pathways, thus causing macrophages to favor the M1 phenotype. Therefore, inhibiting SIK activity can promote the differentiation of innate immune cells into the tolerant M2 type, reduce pro-inflammatory factors such as TNFα, and increase the inflammatory suppressor IL-10. Thus, promoting macrophage differentiation into the immune-tolerant type by inhibiting SIK kinase activity provides a novel therapeutic mechanism for autoimmune diseases.

[0004] Currently, three subtypes of SIK kinase are known: SIK1, SIK2, and SIK3. Studies using mouse gene knockout models have shown that SIK2 and SIK3 play a more significant role in promoting macrophage differentiation. SIK1 is primarily involved in salt metabolism, and SIK1 knockout mice are more sensitive to elevated blood pressure caused by high salt intake. SIK2 knockout mice exhibit a largely normal phenotype, with some elevation in plasma triglycerides; while SIK3 knockout mice have smaller body weight and volume, suggesting a connection to early skeletal development. Although there is currently insufficient research evidence to determine whether the inhibition of SIK kinase by small molecule compounds is consistent with the phenotype of mouse gene knockout, selectively targeting SIK2 / SIK3 while avoiding inhibition of SIK1 is a relatively safe and effective development strategy for SIK small molecule kinase inhibitors developed for autoimmune diseases.

[0005] Currently, the publicly disclosed patents for SIK2 / SIK3 inhibitors include WO2018188785A1, WO2018193084A1, WO2019198940A1, WO2019202160A1, WO2019238424A1, WO2020083926A1, WO2020239658A1, WO2019105886A1, and WO2020239660A1. Summary of the Invention

[0006] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] X 1 Let N, X 2 For C; or, X 1 Let C and X be the values ​​of C and X respectively. 2 Let N be the number of people in the group.

[0010] R 1 -L-(CR) 7 R 8 ) s -AB;

[0011] L is selected from chemical bonds, O, and S;

[0012] A is a heterocyclic group, wherein the heterocyclic group is optionally selected from halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclic, -OR f1 -C(O)R f1 -C(O)OR f1 -NR g1 R h1 -NHC(O)OR f1 -C(O)NR g1 R h1 -S(O)2R J1 -S(O)2NR g1 R h1 It is substituted by one or more substituents among aryl and heteroaryl;

[0013] B is selected from -C(O)R 9 ;

[0014] R 9Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; wherein each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclic, -OR f2 -C(O)R f2 -C(O)OR f2 -NR g2 R h2 -NHC(O)OR f2 -C(O)NR g2 R h2 -S(O)2R J2 -S(O)2NR g2 R h2 It is substituted by one or more substituents among aryl and heteroaryl;

[0015] R 7 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkenyl groups, alkynyl groups, cyano groups, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0016] G 1 For CR 3 Or N atoms;

[0017] R 2 R 3 R 4 and R 6 The same or different, and each independently selected from hydrogen atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0018] R 5 Selected from hydrogen atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy and -NR 5a R 5b The alkenyl, alkynyl, alkyl, and alkoxy groups therein are each optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0019] R 5a and R 5b They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0020] R w For -NR w1 R w2 or -NR w3 -;

[0021] R w1 The group is selected from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0022] R w2 and R w3 The same or different, and each independently selected from hydrogen atoms, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0023] When R w For -NR w3 - At that time, the N atom in it reacts with R 5 Together they form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0024] R f1 and R f2 The same or different, and each independently selected from hydrogen atoms, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0025] R g1 R h1 Rg2 and R h2 The same or different, and each independently selected from hydrogen atoms, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0026] Or R g1 and R h1 With the connected N atom, R g2 and R h2 Together with the connected N atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0027] R J1 and R J2 They may be the same or different, and each is independently selected from hydrogen atoms, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0028] p is 1, 2, or 3;

[0029] s can be 0, 1, 2, 3 or 4.

[0030] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 It is a hydrogen atom.

[0031] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0032]

[0033] in:

[0034] Ring A is a 3- to 12-membered heterocyclic group containing at least one nitrogen atom;

[0035] R 10 They may be the same or different, and each is independently selected from hydrogen, halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclic, cycloalkyloxy, heterocyclicoxy, amino, aryl and heteroaryl;

[0036] R y They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0037] t is 1, 2, or 3;

[0038] n is 0, 1, or 2;

[0039] m can be 0, 1, 2, 3, or 4;

[0040] L, X 1 X 2 G 1 R 2 R 4 R 6 R 9 R w3 p and s are as defined in general formula (I).

[0041] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (III) or general formula (IV) or their pharmaceutically acceptable salts, wherein for R 2 and p as defined in general formula (I); more preferably, for

[0042] In some preferred embodiments of this disclosure, the compounds represented by general formula (I) and general formula (III) or their pharmaceutically acceptable salts, wherein R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 8-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; preferably, R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; more preferably, R 2 It is a hydrogen atom.

[0043] In some preferred embodiments of this disclosure, the compounds represented by general formula (I) and general formula (III) or their pharmaceutically acceptable salts, wherein G 1 For CR 3 ;R 3 As defined in general formula (I); preferably, R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; more preferably, R 3 C 1-6 Alkoxy or C 1-6 Haloalkoxy; more preferably, R 3 C 1-6 Alkyl group; most preferably, R 3 It is a methoxy group.

[0044] In some preferred embodiments of this disclosure, the compounds represented by general formula (I) and general formula (III) or their pharmaceutically acceptable salts, wherein R 4 and R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, nitro groups, hydroxyl groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, amino groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups; preferably, R 4 and R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 4 and R 6 All are hydrogen atoms.

[0045] In some preferred embodiments of this disclosure, the compounds represented by general formula (I) and general formula (III) or their pharmaceutically acceptable salts, wherein R 9 It is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl group and the 3- to 12-membered heterocyclic group are each independently selected independently from halogens, C 2-6 alkenyl, C 2-6 alkynyl, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6It is substituted by one or more of the following: haloalkoxy, oxo, 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclic, 3 to 8-membered cycloalkyloxy, and 3 to 12-membered heteroalkyloxy.

[0046] In some preferred embodiments of this disclosure, the compounds represented by general formula (I) and general formula (III) or their pharmaceutically acceptable salts, wherein R 9 It is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl group and the 3- to 12-membered heterocyclic group are each independently selected independently from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 It is substituted by one or more of the haloalkoxy and oxo groups.

[0047] In some preferred embodiments of this disclosure, the compounds represented by general formula (I) and general formula (III) or their pharmaceutically acceptable salts, wherein R 9 It is a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 The alkoxy group is substituted with one or more of the haloalkoxy and oxo groups; preferably, R 9 It is a 3- to 8-membered cycloalkyl group; more preferably, R 9 It is cyclopropyl.

[0048] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 10 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, R 10 It is a hydrogen atom.

[0049] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen atom, halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups and -NR 5a R 5b The C mentioned therein 1-6 Alkyl and C 1-6 Each alkoxy group is independently selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Substituted by one or more of the following: alkoxy, amino, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; R 5a and R 5b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl;

[0050] Preferably, R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0051] More preferably, R 5 C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0052] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R w1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups and 3- to 8-membered cycloalkyl groups are each independently selected from halogen, cyano, hydroxyl, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Substituted by one or more of the following substituents: haloalkoxy, amino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic and oxo; and / or, R w2 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups and 3- to 8-membered cycloalkyl groups are each independently selected from halogen, cyano, hydroxyl, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy, C 1-6 The substituent is one or more of the following: haloalkoxy, amino, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic and oxo;

[0053] Preferably, R w1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups and 3- to 8-membered cycloalkyl groups are each optionally substituted independently with one or more halogens; and / or, R w2 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups and 3- to 8-membered cycloalkyl groups are each optionally substituted independently with one or more halogens;

[0054] More preferably, R w1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups; and / or, R w2 It is a hydrogen atom;

[0055] More preferably, R w1 Cyclopropyl; and / or, R w2 It is a hydrogen atom.

[0056] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R w3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups and 3- to 8-membered cycloalkyl groups are each independently selected from halogen, cyano, hydroxyl, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 The substituent is one or more of the following: haloalkoxy, amino, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups;

[0057] Preferably, R w3 C 1-6 Halogenated alkyl groups;

[0058] More preferably, R w3 It is -CH2CF3.

[0059] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0060] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or its pharmaceutically acceptable salt is used, wherein m is 0.

[0061] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, hydroxyl groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy and amino groups;

[0062] Preferably, R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl;

[0063] More preferably, R y It is a hydrogen atom.

[0064] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) or its pharmaceutically usable salt is used, wherein s is 0, 1 or 2.

[0065] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) or its pharmaceutically usable salt, wherein L is a chemical bond or O.

[0066] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) or its pharmaceutically acceptable salt, wherein L is a chemical bond; and / or, s is 0.

[0067] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein L is O or S; and / or, s is 1 or 2;

[0068] Preferably, L is 0; and / or, s is 2.

[0069] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) or its pharmaceutically usable salt, wherein p is 1.

[0070] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or its pharmaceutically usable salt is used, wherein t is 1.

[0071] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for W is C, CH, or N; It can be a single or double bond; R 10 And t is as defined in general formula (III);

[0072] Preferably, for R 10 And t is as defined in general formula (III);

[0073] More preferably, for

[0074] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein X 1 Let C and X be the values ​​of C and X respectively. 2 For N; or, X 1 Let N, X 2 C; L is selected from chemical bonds, O, and S; ring A is a 3- to 12-membered heterocyclic group containing at least one nitrogen atom; R 2 For hydrogen atoms; G 1 For CR 3 ;R 3 C 1-6 Alkoxy; R 4 and R 6 All are hydrogen atoms; R 10 For hydrogen atoms; R 9 It is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl group and the 3- to 12-membered heterocyclic group are each independently selected independently from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 It is substituted by one or more substituents among the haloalkoxy and oxo groups; R w3 C 1-6 Haloalkyl; s is 0, 1 or 2; n is 1; R y For hydrogen atoms; t is 1.

[0075] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for for R 4 and R 6 All are hydrogen atoms; R 9 It is a 3- to 8-membered cycloalkyl group; s is 0, 1, or 2; L is a chemical bond or O; G 1 For CR 3 ;R3 C 1-6 Alkoxy; R w3 C 1-6 Haloalkyl; n is 1; m is 0.

[0076] Table A lists typical compounds disclosed herein, including but not limited to:

[0077]

[0078]

[0079]

[0080] Furthermore, this disclosure provides a compound of general formula (IIIA) or a salt thereof:

[0081]

[0082] in:

[0083] R 10 It is a hydrogen atom;

[0084] Rings A, L, X 1 X 2 G 1 R 2 R 4 R 6 R w3 R y m, n, p, s and t are as defined in general formula (III).

[0085] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0086]

[0087]

[0088] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0089]

[0090] A compound of general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IIB) or a salt thereof to give a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0091] in:

[0092] X is a halogen; preferably Cl;

[0093] Rings A, L, X1 X 2 G 1 R 2 R 4 R 6 R 9 R 10 R w3 R y m, n, p, s and t are as defined in general formula (III).

[0094] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (III) or Table A of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0095] This disclosure further relates to the use of compounds of general formula (I), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for inhibiting SIK2 and / or SIK3.

[0096] This disclosure further relates to the use of compounds of general formula (I), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and / or preventing diseases or conditions, wherein said diseases or conditions are 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 TNFα, interferon, IL-6, IL-12 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and diseases related to abnormal angiogenesis; preferably, said diseases or conditions are inflammatory diseases. The inflammatory disease or autoimmune disease; more preferably, the inflammatory disease 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 (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease, Sjögren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and related complications, atopic eczema, thyroiditis, contact dermatitis, Sjögren's syndrome and amyotrophic lateral sclerosis; wherein the inflammatory bowel disease is preferably ulcerative colitis and Crohn's disease.

[0097] This disclosure further relates to a method of inhibiting SIK2 and / or SIK3, comprising administering to a patient a therapeutically effective amount of a compound of general formula (I), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0098] This disclosure further relates to a method of treating and / or preventing a disease or condition, comprising administering to a desired patient a therapeutically effective amount of a compound of general formula (I), general formula (III), or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving chondrodysplasia, congenital chondrodysplasia, diseases involving bone turnover, diseases associated with excessive secretion of TNFα, interferon, IL-6, IL-12, and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and diseases related to abnormal angiogenesis; preferably, wherein the disease or condition is selected from inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving chondrodysplasia, congenital chondrodysplasia, diseases involving bone turnover, diseases associated with excessive secretion of TNFα, 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 the disease or condition is selected from inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, and diseases involving excessive secretion of TNFα, interferon, IL-6, IL-12, and / or IL-23, and pharmaceutically acceptable diseases. The disease is an inflammatory disease or an autoimmune disease; more preferably, the inflammatory disease 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 (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease, Sjögren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and related complications, atopic eczema, thyroiditis, contact dermatitis, Sjögren's syndrome, and amyotrophic lateral sclerosis; wherein the inflammatory bowel disease is preferably ulcerative colitis and Crohn's disease.

[0099] This disclosure further relates to a compound of general formula (I), general formula (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0100] This disclosure further relates to a compound of general formula (I), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which acts as a medicament for inhibiting SIK2 and / or SIK3.

[0101] This disclosure further relates to a compound of general formula (I), general formula (III), or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, used as a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is 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 TNFα, interferon, IL-6, IL-12, and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and diseases related to abnormal angiogenesis; preferably, wherein the disease or condition is an inflammatory disease. The inflammatory disease 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 (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease, Sjögren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and related complications, atopic eczema, thyroiditis, contact dermatitis, Sjögren's syndrome, and amyotrophic lateral sclerosis; wherein the inflammatory bowel disease is preferably ulcerative colitis and Crohn's disease.

[0102] The aforementioned diseases or conditions are preferably SIK2 and / or SIK3 mediated diseases or conditions.

[0103] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of this disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0104] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0105] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0106] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0107] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0108] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, 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 sweeteners.

[0109] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0110] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0111] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0112] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0113] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0114] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0115] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the severity of the disease, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, and the severity of the disease; in addition, the optimal treatment mode, such as the treatment regimen, the daily dosage of the compound, or the type of pharmaceutically acceptable salt, can be validated based on conventional treatment protocols.

[0116] Terminology Explanation

[0117] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0118] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms (i.e., C1646-C ... 1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably selected independently from one or more substituents chosen from the D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0119] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Preferably, it is an alkenyl compound containing 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C14-C14-C14). 2-12 Alkenyl), more preferably alkenyl containing 2 to 6 carbon atoms (i.e., C14-C ... 2-6 Alkenyl). The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl substituents.

[0120] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. Preferably, the alkynyl group (i.e., C14) contains 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12). 2-12Alkyne group), more preferably an alkyne group containing 2 to 6 carbon atoms (i.e., C12-C6 ... 2-6 (Alkyne). The alkynyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0121] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably 3 to 14 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) (i.e., 3 to 14-membered cycloalkyl), more preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8-membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0122] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds (i.e., 5- to 20-membered spirocycloalkyl). Preferably, it is 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 as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, 5 / 6-membered, or 6 / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0123]

[0124] The term "fused cycloalkyl" refers to a 5- to 20-membered 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 rings may contain one or more double bonds (i.e., 5- to 20-membered fused cycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered fused cycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered fused cycloalkyl). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3- / 4-membered, 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 4-membered, 5- / 5-membered, 5- / 6-membered, 6- / 3-membered, 6- / 4-membered, 6- / 5-membered, and 6- / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include:

[0125]

[0126] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds (i.e., 5- to 20-membered bridged cycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered bridged cycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged cycloalkyl). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0127]

[0128] The cycloalkyl ring includes cycloalkyl groups (including monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferably

[0129] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0130] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0131] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon (i.e., 3 to 20 membered heterocyclic groups). Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3 to 12-membered heterocyclic groups); more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms (i.e., 3 to 8-membered heterocyclic groups); even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclic groups); most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms (i.e., 5 or 6-membered heterocyclic groups). Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0132] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may be optionally oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds (i.e., a 5- to 20-membered spiroheterocyclic group). Preferably, it is 6- to 14-membered (i.e., a 6- to 14-membered spiroheterocyclic group), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., a 7- to 10-membered spiroheterocyclic group). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between the rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic group. Non-limiting examples of spiroheterocyclic groups include:

[0133]

[0134] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., 5- to 20-membered fused heterocyclic groups). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered fused heterocyclic groups), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered fused heterocyclic groups). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, tetracyclic, or multicyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably ternary / quadricyclic, ternary / pentacyclic, ternary / hexacyclic, quadricyclic / quadricyclic, quadricyclic / pentacyclic, quadricyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, and pentacyclic / pentacyclic bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0135]

[0136]

[0137] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5- to 14-membered bridged heterocyclic group). Preferably, it is a 6- to 14-membered group (i.e., a 6- to 14-membered bridged heterocyclic group), more preferably a 7- to 10-membered group (e.g., 7, 8, 9, or 10-membered group) (i.e., a 7- to 10-membered bridged heterocyclic group). Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0138]

[0139] The heterocyclic ring comprises a heterocyclic group (including monocyclic heterocyclic groups, spirocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0140] wait.

[0141] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0142] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system (i.e., 6- to 14-membered aryl), 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. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0143]

[0144] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0145] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen (i.e., 5 to 14-membered heteroaryls). The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) (i.e., 5 to 10-membered heteroaryls), more preferably 5 or 6-membered (i.e., 5 or 6-membered heteroaryls), such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl ring fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0146]

[0147] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0148] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0149] The term "amino protecting group" is a group that is easily removed to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include, but are not limited to, (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, allyl, and p-methoxybenzyl. These groups may optionally be substituted with 1 to 3 substituents selected from halogens, alkoxy groups, and nitro groups.

[0150] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0151] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0152] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0153] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0154] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0155] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0156] The term "hydroxyl group" refers to -OH.

[0157] The term "amino" refers to -NH2.

[0158] The term "cyano" refers to -CN.

[0159] The term "nitro" refers to -NO2.

[0160] The term "oxo" or "oxo" refers to "=O".

[0161] The term "carbonyl" refers to C=O.

[0162] The term "carboxyl group" refers to -C(O)OH.

[0163] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0164] “Boc” refers to tert-butyloxycarbonyl.

[0165] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0166] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include and Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0167] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0168]

[0169] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0170]

[0171] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0172] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0173] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0174] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher. "Optional" or "optionally" means that the event or environment subsequently described may, but is not necessarily, occur; this description includes the possibility that the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic groups" means that alkyl groups may but are not required to be present. This description includes cases where heterocyclic groups are substituted with alkyl groups and cases where heterocyclic groups are not substituted with alkyl groups.

[0175] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0176] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0177] "Pharmacologically acceptable salts" refer to salts of the compounds disclosed herein that are safe and effective in mammalian use and possess the intended biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting suitable groups with suitable bases or acids. 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 both inorganic and organic acids.

[0178] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0179] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0180] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0181] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only and not as limitations.

[0182] The term "inflammatory condition" refers to diseases or conditions including: 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 disease (e.g., Crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., complications after bypass surgery 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.

[0183] The term "autoimmune disease" refers to diseases or conditions including: obstructive airway diseases, including conditions such as COPD, asthma (e.g., intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma), especially chronic or refractory asthma (e.g., advanced asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g., autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis), Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis), contact dermatitis, inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis), Sjögren's syndrome, and amyotrophic lateral sclerosis. Preferably, the term refers to COPD, asthma, systemic lupus erythematosus, type 1 diabetes, and inflammatory bowel disease.

[0184] The term "diseases involving cartilage transformation damage" 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, Tietze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neurogenic arthritis, arthropathy, endemic arthritis such as endemic degenerative osteoarthritis, Mseleni disease and Handigodu disease; degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0185] 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 caused by proliferative bone marrow disorders, osteopenia, hormone deficiencies (vitamin D deficiency, male and female hypogonadism), hormone excesses (hyperprolactinemia, excessive glucocorticoids, hyperthyroidism, hyperparathyroidism), Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatase syndrome.

[0186] The term “diseases associated with excessive secretion of TNF, interferon, IL-12 and / or IL-23” includes conditions such as: systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis and / or Crohn's disease.

[0187] The term "respiratory disease" refers to diseases affecting organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphragm and intercostal spaces), and nerves. Preferably, examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal 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.

[0188] The term "proliferative disorder" refers to conditions such as cancer, myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis), and fibrosis. Preferably, the term refers to cancer.

[0189] The term "cancer" includes leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, stomach cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar 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 cancers. For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0190] The method for synthesizing the compounds disclosed herein

[0191] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0192] Option 1

[0193] A method for preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0194]

[0195] (a) The compound of general formula (IIIC) or its salt, under acidic conditions, is deamino protecting to give the compound of general formula (IIIA) or its salt.

[0196] (b) A compound of general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IIB) or a salt thereof in the presence of a base to give a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0197] in:

[0198] M is an amino protecting group, preferably Boc;

[0199] X is a halogen; preferably Cl;

[0200] Rings A, L, X 1 X 2 G 1 R 2 R 4 R 6 R 9 R 10 R w3 R y m, n, p, s and t are as defined in general formula (III).

[0201] In the reaction of step (a) above, the reagents providing acidic conditions include organic acids and inorganic acids. The organic acids include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf; the inorganic acids include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Preferably, the reagent providing acidic conditions is a 1,4-dioxane solution of hydrogen chloride.

[0202] In step (b) above, the reagents providing alkaline conditions include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide. Preferably, the reagent providing alkaline conditions is triethylamine.

[0203] The reactions in steps (a) and (b) above are preferably carried out in a solvent, which includes, but is 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,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof, preferably dichloromethane. Detailed Implementation

[0204] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0205] Example

[0206] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard.

[0207] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0208] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0209] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive)

[0210] High-performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

[0211] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0212] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0213] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0214] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0215] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0216] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0217] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0218] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0219] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0220] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0221] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0222] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0223] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0224] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0225] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0226] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0227] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0228] Example 1

[0229] 6-(6-(2-(4-(cyclopropylcarbonyl)piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one

[0230]

[0231] first step

[0232] 6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 1c

[0233] 6-Bromo-3-iodopyrazolo[1,5-a]pyridine 1a (2 g, 6.19 mmol, prepared by the method disclosed in intermediate 15 on page 145 of patent application WO2019105886A1), and 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 1b (2.9 g, 7.5 mmol) were prepared. 2 mmol (prepared using the method disclosed in intermediate 14 on page 70 of patent application WO2020239660A1), cesium carbonate (6 g, 18.42 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (450 mg, 0.62 mmol) were suspended in 120 mL of a mixed solution of 1,4-dioxane and water (V:V = 5:1). The mixture was heated to 90 °C and stirred for 8 hours under nitrogen protection. After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel column chromatography using eluent system B to give title compound 1c (2.4 g, yield: 85.3%).

[0234] MS m / z(ESI):456.0[M+2].

[0235] Step 2

[0236] 8-Methoxy-6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)pyrazolo[1,5-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1-(2H)-one 1d

[0237] (3-(8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazolo[1,5-a]pyridin-6-yl)boronic acid 1e

[0238] Compound 1c (280 mg, 0.62 mmol), pinacol diboronate (188 mg, 0.74 mmol), potassium acetate (182 mg, 1.85 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (45 mg, 0.06 mmol) were heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel column chromatography using eluent system A to give a mixture (300 mg) of title compounds 1d and 1e.

[0239] 1d MS m / z(ESI):502.1[M+1].

[0240] 1e MS m / z(ESI):420.2[M+1].

[0241] Step 3

[0242] 6-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 1f

[0243] A mixture of compounds 1d and 1e (300 mg) was dissolved in tetrahydrofuran (20 mL). Hydrogen peroxide (204 mg, 1.79 mmol, 30% purity) was added dropwise under ice bath conditions. The mixture was stirred for 10 minutes, followed by the addition of sodium hydroxide solution (0.3 M, 2 mL). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 1f (200 mg, yield: 85.3%).

[0244] MS m / z(ESI):392.1[M+1].

[0245] Step 4

[0246] 4-(2-((3-(8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester 1h

[0247] Compound 1f (200 mg, 0.51 mmol), 1 g of tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (165 mg, 0.56 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), and cesium carbonate (333 mg, 1.02 mmol) were suspended in N,N-dimethylformamide (5 mL) and stirred at 80 °C for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel column chromatography using eluent system A to give the title compound 1h (300 mg, yield: 97.2%).

[0248] MS m / z(ESI): 604.2 [M+1].

[0249] Step 5

[0250] 8-Methoxy-6-(6-(2-(piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one hydrochloride 1i

[0251] Compound 1h (300 mg, 0.49 mmol) was dissolved in 2 mL of dichloromethane, and a 1,4-dioxane solution of hydrogen chloride (4 M, 5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give the title compound 1i (268 mg, yield: 99.8%). The product was directly used in the next reaction without purification.

[0252] MS m / z(ESI):504.1[M+1].

[0253] Step 6

[0254] 6-(6-(2-(4-(cyclopropylcarbonyl)piperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one

[0255] Compound 1i (268 mg, 0.49 mmol, hydrochloride) was suspended in 20 mL of dichloromethane, and triethylamine (151 mg, 1.49 mmol) and cyclopropylformyl chloride 1j (78 mg, 0.74 mmol, Alfaesa (China) Chemical Co., Ltd.) were added. The mixture was stirred at room temperature for 1 hour and purified by high performance liquid chromatography (HPLC) (column: SharpSil-T Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; gradient: 30%-50%, flow rate: 30 mL / min) to give title product 1 (70 mg, yield: 24.6%). MS m / z (ESI): 572.2 [M+1].

[0256] 1 H NMR(500MHz,CD3OD)δ8.30(s,1H),8.25(s,1H),7.92(d,1H),7.24-7.21(m,2H),7.14(s,1H),4.34(q,2H),4.22(t,2H),3.97(s,3H),3.8 3(brs,2H),3.71(t,2H),3.66(brs,2H),3.05(t,2H),2.92(t,2H),2.70(brs,2H),2.62(brs,2H),2.00-1.95(m,1H),0.93-0.81(m,4H).

[0257] Example 2

[0258] 6-(6-(1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 2

[0259]

[0260]

[0261] first step

[0262] 4-(3-(8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazolo[1,5-a]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-formate tert-butyl ester 2b

[0263] Compound 1c (300 mg, 0.66 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 2a (245 mg, 0.79 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (48 mg, 0.06 mmol), and anhydrous potassium carbonate (183 mg, 1.32 mmol) were suspended in a mixed solution of 1,4-dioxane and water (V:V = 5:1, 25 mL). The mixture was stirred at 100 °C for 8 hours under nitrogen protection. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 2b (370 mg, yield: 100%).

[0264] MS m / z(ESI): 557.1 [M+1].

[0265] Step 2

[0266] 8-Methoxy-6-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one hydrochloride 2c

[0267] Compound 2b (100 mg, 0.17 mmol) was dissolved in 2 mL of dichloromethane, and a 4 M, 5 mL solution of 1,4-dioxane hydrogen chloride was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give the title compound 2c (88 mg, yield: 99.3%). The product was used directly for the next reaction without purification.

[0268] MS m / z(ESI):457.1[M+1].

[0269] Step 3

[0270] 6-(6-(1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 2

[0271] Compound 2c (40 mg, 0.08 mmol, hydrochloride) was dissolved in 20 mL of dichloromethane, and triethylamine (27 mg, 0.26 mmol) and cyclopropylformyl chloride 1i (13 mg, 0.124 mmol) were added. The mixture was stirred at room temperature for 1 hour and purified by high performance liquid chromatography (column: SharpSil-T Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; gradient: 35%-55%, flow rate: 30 mL / min) to give title product 2 (25 mg, yield: 54.3%).

[0272] MS m / z(ESI): 525.2 [M+1].

[0273] 1 H NMR(500MHz,DMSO-d6)δ8.76(s,1H),8.55(d,1H),8.08(d,1H),7.65(t,1H),7.24(d,2H),6.47-6.37(m,1H),4.45(s,1H),4.34(q,2H),4.1 8(s,1H),3.91(m,4H),3.73(s,1H),3.62(t,2H),3.00(t,2H),2.68(s ,1H),2.55(s,1H),2.10(s,0.5H),1.99(s,0.5H),0.78-0.74(m,4H).

[0274] Example 3

[0275] 6-(7-(2-(4-(cyclopropylcarbonyl)piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one3

[0276]

[0277] first step

[0278] 6-(7-Fluorimidazolo[1,2-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 3c

[0279] Compound 7-fluoroimidazolo[1,2-a]pyridine 3a (350 mg, 2.57 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) was dissolved in N,N-dimethylacetamide (10 mL), and 6-bromo-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 3b (870 mg, 2.57 mmol, prepared by the method disclosed in intermediate 39 on page 162 of patent application WO2019238424A1), potassium acetate (631 mg, 6.43 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (180 mg, 0.25 mmol) were added. The mixture was heated to 120 °C and stirred for 3 hours under a nitrogen atmosphere. After cooling to room temperature and concentrating under reduced pressure, the residue was purified by silica gel column chromatography with eluent system D to give the title compound 3c (750 mg, yield: 74.2%).

[0280] MS m / z(ESI):394.1[M+1].

[0281] Step 2

[0282] 4-(2-((3-(8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline)-6-yl)imidazo[1,2-a]pyridin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester 3e

[0283] 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester 3d (1.60 g, 6.95 mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 15 mL of N,N-dimethylformamide. Sodium hydride (270 mg, 7.05 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was added in portions, and the mixture was stirred at room temperature for 30 minutes. Then, compound 3c (450 mg, 1.14 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 20 mL of saturated sodium bicarbonate solution, and extracted with ethyl acetate (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3e (650 mg, yield: 94.1%).

[0284] MS m / z(ESI): 604.2 [M+1].

[0285] Step 3

[0286] 8-Methoxy-6-(7-(2-(piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 3f

[0287] Compound 3e (0.65 g, 1.1 mmol) was dissolved in 15 mL of dichloromethane, and a solution of 1,4-dioxane (4 M, 2.7 mL) containing hydrogen chloride was added. The mixture was stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure to give the title compound 3f (500 mg, yield: 92.2%), which was used directly in the next step without purification.

[0288] MS m / z(ESI): 504.2 [M+1].

[0289] Step 4

[0290] 6-(7-(2-(4-(cyclopropylcarbonyl)piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one3

[0291] Compound 3f (500 mg, 0.87 mmol) was dissolved in 20 mL of dichloromethane, and triethylamine (890 mg, 8.8 mmol) and compound 1j (181 mg, 1.73 mmol) were added. The mixture was stirred at room temperature for 10 min and purified by high performance liquid chromatography (column: SharpSil-T Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; gradient: 32%-52%, flow rate: 30 mL / min) to give title product 3 (230 mg, yield: 46.4%).

[0292] MS m / z(ESI): 572.3 [M+1].

[0293] 1 H NMR(500MHz,DMSO-d6)δ8.59(d,1H),7.77(s,1H),7.19(d,1H),7.16(s,1H),7.10(s,1H),6.72(dd,1H),4.35(dd,2H),4.23(t,2H),3.88(s,3H ),3.69(brs,2H),3.63(t,2H),3.48(brs,2H),2.99(t,2H),2.80(t,2H),2.52(brs,2H),2.47(brs,2H),1.95-2.00(m,1H),0.68-0.74(m,4H).

[0294] Example 4

[0295] 8-Methoxy-6-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one

[0296]

[0297] first step

[0298] 8-Methoxy-6-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one

[0299] Compound 2c (50 mg, 0.1 mmol) was dissolved in methanol (5 mL), followed by the addition of glacial acetic acid (18 mg, 0.3 mmol), anhydrous sodium acetate (33 mg, 0.4 mmol), and a 37% aqueous formaldehyde solution (26 mg, 0.3 mmol). The mixture was stirred at room temperature for 30 minutes, followed by the addition of sodium cyanoborohydride (12 mg, 0.2 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was purified by high-performance liquid chromatography (HPLC) (column: SharpSil-T Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 12-minute gradient, acetonitrile phase 44%-56%, flow rate: 30 mL / min) to give title product 4 (24 mg, yield: 50.0%).

[0300] MS m / z(ESI):471.7[M+1].

[0301] 1 H NMR(500MHz,DMSO-d6)δ8.69(s,1H),8.53(s,1H),8.05(d,1H),7.64(dd,1H),7.26-7.19(m,2H),6.41-6.35(m,1H),4.3 4(q,2H),3.90(s,3H),3.62(t,2H),3.08-3.04(m,2H),2.99(t,2H),2.62-2.58(m,2H),2.58-2.54(m,2H),2.30(s,3H).

[0302] Example 5

[0303] 6-(6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 5

[0304]

[0305] first step

[0306] 6-(6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one 5

[0307] Compound 2c (80 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (106 mg, 0.3 mmol) and iodoethane (31 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 5 hours. Purification was performed by high-performance liquid chromatography (HPLC) (column: SharpSil-T Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 20-minute gradient, acetonitrile phase 45%-65%, flow rate: 30 mL / min) to give title product 5 (30 mg, yield: 38%).

[0308] MS m / z(ESI): 485.8 [M+1].

[0309] 1 H NMR(500MHz,CD3OD)δ8.68(s,1H),8.40(s,1H),8.01(d,1H),7.64(dd,1H),7.25(d,1H),7.19(d,1H),6.41-6.35(m,1H),4.36(q ,2H),4.26-4.08(m,2H),3.98(s,3H),3.95-3.78(m,2H),3.73(t,2H),3.38(q,2H),3.08(t,2H),2.99-2.94(m,2H),1.46(t,3H).

[0310] Example 6

[0311] 8-Methoxy-6-(6-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one6

[0312]

[0313] first step

[0314] 8-Methoxy-6-(6-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one6

[0315] Compound 2c (100 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (286 mg, 0.88 mmol) and 1-iodopropane (56 mg, 0.33 mmol) were added. The mixture was stirred at 50 °C for 2 hours. Purification was performed by high-performance liquid chromatography (HPLC) (column: YMC Triart-Exrs Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 48%-63%, flow rate: 30 mL / min) to give title product 6 (40 mg, yield: 36.6%). MS m / z (ESI): 499.8 [M+1].

[0316] 1 H NMR(500MHz,DMSO-d6)δ8.69(s,1H),8.53(s,1H),8.05(d,1H),7.63(dd,1H),7.29-7.19(m,2H),6.47-6.34(m,1H),4.34(q,2H),3.90( s,3H),3.63(t,2H),3.13-3.08(m,2H),2.99(t,2H),2.64(t,2H),2.57-2.53(m,2H),2.37(t,2H),1.57-1.46(m,2H),0.96-0.83(m,3H).

[0317] Example 7

[0318] 6-(6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one7

[0319]

[0320] first step

[0321] 6-(6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one7

[0322] Compound 2c (100 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (286 mg, 0.88 mmol) and 2-iodopropane (56 mg, 0.33 mmol) were added. The mixture was stirred at 80 °C for 5 hours. The product was purified by high-performance liquid chromatography (HPLC) (column: SharpSil-T Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 20-minute gradient, acetonitrile phase 40%-60%, flow rate: 30 mL / min) to give title product 7 (45 mg, yield: 44.5%).

[0323] MS m / z(ESI):499.2[M+1].

[0324] 1 H NMR(500MHz,DMSO-d6)δ8.68(s,1H),8.53(s,1H),8.05(d,1H),7.63(dd,1H),7.27-7.19(m,2H),6.42-6.37(m,1H),4.34(q,2 H),3.90(s,3H),3.62(t,2H),3.24-3.19(m,2H),2.99(t,2H),2.81-2.75(m,1H),2.69(t,2H),2.55-2.52(m,2H),1.05(d,6H).

[0325] Example 8

[0326] 6-(6-(1-(cyclopropylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one8

[0327]

[0328] first step

[0329] 6-(6-(1-(cyclopropylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline-1(2H)-one8

[0330] Compound 2c (100 mg, 0.22 mmol) was dissolved in methanol (5 mL), followed by the addition of glacial acetic acid (37 mg, 0.62 mmol), anhydrous sodium acetate (34 mg, 0.42 mmol), and cyclopropaneformaldehyde (22 mg, 0.3 mmol). The mixture was stirred at room temperature for 30 min, and then sodium cyanoborohydride (25 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 30 h. The product was purified by high performance liquid chromatography (HPLC) (column: YMC Triart-Exrs Prep C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 47%-62%, flow rate: 30 mL / min) to give title product 8 (40 mg, yield: 38.6%). MS m / z (ESI): 511.8 [M+1].

[0331] 1 H NMR(500MHz,DMSO-d6)δ8.69(s,1H),8.53(s,1H),8.05(d,1H),7.63(dd,1H),7.27-7.21(m,2H),6.45-6.33(m,1H),4.34(q,2H),3.91(s,3H), 3.62(t,2H),3.23-3.17(m,2H),2.99(t,2H),2.71(t,2H),2.56(m,2H) ,2.32(d,2H),0.95-0.83(m,1H),0.55-0.48(m,2H),0.17-0.10(m,2H).

[0332] Biological evaluation

[0333] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0334] Test Example 1: Inhibitory effect of the disclosed compound on human SIK1 kinase

[0335] I. Experimental Materials and Instruments

[0336] 1. SIK1 enzyme (Carna, 02-131)

[0337] 2. AMARA(GL,226536)

[0338] 3. DMSO (Sigma, D2650)

[0339] 4. 96-hole plate (Corning, 3365)

[0340] 5. 384-orifice plate (Corning, 3573)

[0341] 6. Staurosporine (MCE, HY-15141)

[0342] 7. ATP (Sigma, 2383-5g)

[0343] 8. Magnesium chloride (Sigma, M2670-500g)

[0344] 9. DTT (Sigma, D0632-10g)

[0345] 10.Triton X-100 (Sigma, T9284-100 mL)

[0346] 11. Hepes (Gibco, 11344-041)

[0347] 12. Brij-35 solution (Sigma, B4184-100 mL)

[0348] 13. EDTA (Gibco, 15575-038)

[0349] 14. Coating Reagent #3 (Perkin Elmer)

[0350] 15.Caliper EZ Reader No.2 (Perkin Elmer)

[0351] 16. Precision Automated Pipetting and Dispensing System (BioTek)

[0352] 17. Incubator (Shanghai Boxun)

[0353] II. Experimental Procedure

[0354] SIK1 is a kinase that phosphorylates the substrate AMARA in the presence of ATP. A mobility shift assay can be used to detect changes in SIK1 enzyme activity. Using FAM-labeled AMARA as the substrate, in the presence of ATP, AMARA is phosphorylated and acquires a phosphate group. This product differs from the unphosphorylated substrate by three negative charges. The resulting liquid is aspirated into a microfluidic chip, and the AMARA substrate and product enter an electrically charged capillary, migrating towards the positive electrode. Because the peptide product carries phosphate ions, its migration rate is faster, thus separating the remaining substrate and product. Finally, a fluorescence detection system is used to calculate the peak ratio of the product to the remaining substrate, thereby detecting changes in enzyme activity.

[0355] The 20 mM test compound dissolved in 100% DMSO was diluted to 500 μM with 100% DMSO. This is 50 times the highest concentration of the compound in the reaction system. This concentration of compound was serially diluted 4 times with 100% DMSO to nine concentration points, for a total of 10 concentration points. The blank wells were filled with 100% DMSO. The serially diluted compound and 100% DMSO were then further diluted 10 times to 5X concentration in 1X kinase buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT, 0.01% Triton X-100) and mixed thoroughly. 5 μL of the 5X concentration of compound was added to the reaction wells. 5 μL of 10% DMSO was added to the negative control wells (no enzyme added) and the positive control wells (enzyme added, no compound added). Dilute SIK1 enzyme to a 2.5-fold concentration (final reaction concentration 18 nM) in 1X kinase buffer, transfer 10 μL of the enzyme dilution to the reaction system, and incubate at room temperature for 10 minutes. Dilute AMARA and ATP to a 2.5-fold concentration (final reaction concentration of AMARA 3 μM, final reaction concentration of ATP 128 μM) in 1X kinase buffer, transfer 10 μL of substrate and ATP solution to the reaction system, mix well, and react at 28 degrees Celsius for 60 minutes. Add 25 μL of stop solution (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% coating reagent #3, 50 mM EDTA).

[0356] The reaction product was read on a Caliper instrument, and the resulting value was calculated as the inhibition rate using the following formula: Inhibition rate = (Positive control value - Test well value) / (Positive control value - Negative control value) * 100. A curve was fitted on XLFit version 5.4.0.8, and the IC50 concentration of the compound at 50% inhibition was calculated. 50 See Table 1.

[0357] Table 1. IC50 of the disclosed compounds on human SIK1 enzyme inhibition. 50 value

[0358] 1 634 96 2 206 98 3 1245 91 4 561 94 6 466 97 7 628 96 8 469 96

[0359] Conclusion: The compound disclosed herein has a weak inhibitory effect on SIK1.

[0360] Test Example 2

[0361] Test Example 2: Inhibitory effect of the disclosed compound on human SIK2 kinase

[0362] I. Experimental Materials and Instruments

[0363] 1. SIK2 enzyme (Promega, VA7267)

[0364] 2. ADP-Glo TMKinase reagent (Promega, V9101)

[0365] 3. DMSO (Sigma, D2650)

[0366] 4. Magnesium chloride solution (Sigma, M1028-100ML)

[0367] 5. Tris pH 7.5 2M (Beyotime, B548139-0500)

[0368] 6.Triton X-100(Sigma,T8787-100ML)

[0369] 7. EGTA (Sigma, E3889-100G)

[0370] 8. DTT 2M (Sangon Biotech, B645939)

[0371] 9. 96-Orifice Plate (Corning, 3795)

[0372] 10. 384-orifice plate (Corning, 4513)

[0373] 11. Sterile pure water (manufactured by Shanghai Hengrui)

[0374] 12.15mL centrifuge tube (Corning)

[0375] 13. Incubator (Shanghai Yiheng Scientific Instruments Co., Ltd.)

[0376] 14. Pherastar FS Microplate Reader (BMG Labtech)

[0377] II. Experimental Procedure

[0378] SIK2 is a kinase that phosphorylates the substrate AMARA in the presence of ATP. The ADP-Glo ​​assay kit is a luminescent ADP assay kit used to detect changes in SIK2 enzyme activity. The kit operates in three steps: 1) AMARA, as a substrate, is phosphorylated to produce ADP in the presence of ATP; 2) After the ADP generation reaction is complete, the ADP-Glo ​​reagent is added to terminate the reaction and consume any remaining ATP; 3) The kinase assay reagent is added, converting ADP to ATP while simultaneously converting ATP into a light signal in a coupled luciferase / luciferin reaction, thus detecting changes in enzyme activity.

[0379] The 20 mM test compound dissolved in 100% DMSO was diluted to 1 mM with 100% DMSO. This is 100 times the highest concentration of the compound in the reaction system. This concentration of the compound was serially diluted 4 times with 100% DMSO to 10 concentration points. The blank wells were filled with 100% DMSO. The above serially diluted compound and 100% DMSO were then diluted 20 times in water to a 5X concentration and thoroughly mixed. 1 μL of the 5X concentration of the compound was placed in the reaction wells. 1 μL of 5% DMSO was added to the negative control wells (without enzyme) and the positive control wells (with enzyme and no compound). SIK2 enzyme and AMARA were diluted 2.5-fold in reaction buffer (25 mM Tris, pH 7.5, 0.01% Triton X-100, 0.5 mM EGTA, 5 mM magnesium chloride, 2.5 mM DTT) to a final concentration of SIK2: 0.37 nM; AMARA: 45 μM. 2 μL of the enzyme-substrate dilution was added to the reaction mixture. ATP was diluted 2.5-fold in reaction buffer to a final concentration of 5 μM, and 2 μL was added to the reaction mixture. The 5 μL reaction mixture was thoroughly mixed and incubated at room temperature for 120 minutes. 5 μL of ADP-Glo ​​reagent was added to terminate the reaction, and the mixture was incubated at room temperature for 40 minutes to deplete the remaining ATP. Then, 10 μL of kinase assay reagent was added, and the mixture was incubated at room temperature for 30 minutes. The values ​​were then read, and the inhibition rate was calculated using the following formula: Inhibition rate = 100 - 100 * (Test well value - Negative control value) / (Positive control value - Negative control value). Inhibition curves were plotted using Graphpad Prism software based on the concentrations of the compounds and their corresponding inhibition rates. The concentration of the compound at which the inhibition rate reached 50%, i.e., the IC50 value, was then calculated. 50 The values ​​are shown in Table 2.

[0380] Table 2 IC50 of the disclosed compounds on human SIK2 enzyme inhibition 50 value

[0381] 1 7 100 2 14 100 3 17 100 4 8 97 5 11 101 6 10 101 7 10 102 8 10 101

[0382] Conclusion: The compound disclosed herein exhibits excellent inhibitory activity against SIK2. A comparison of Test Example 1 and Test Example 2 demonstrates that the compound disclosed herein exhibits selective inhibitory activity against SIK2.

[0383] Test Example 3: Inhibitory effect of the disclosed compound on human SIK3 kinase

[0384] I. Experimental Materials and Instruments

[0385] 1. SIK3 enzyme (Promega, VA7300)

[0386] 2. ADP-Glo TMKinase Assay (Promega, V9101)

[0387] 3. DMSO (Sigma, D2650)

[0388] 4. Magnesium chloride solution (Sigma, M1028-100ML)

[0389] 5. Tris PH7.5 2M (Beyond the Sky, B548139-0500)

[0390] 6.Tritoon X-100(Sigma,T8787-100ML)

[0391] 7. EGTA (Sigma, E3889-100G)

[0392] 8. DTT 2M (Sangon Biotech, B645939)

[0393] 9. 96-well plate(Corning,3795)

[0394] 10. 384-well plate(Corning,4513)

[0395] 11. Sterile pure water (manufactured by Shanghai Hengrui)

[0396] 12. 15mL centrifuge tubes (Corning)

[0397] 13. Incubator (Shanghai Yiheng Scientific Instruments Co., Ltd.)

[0398] 14. Pherastar FS Microplate Reader (BMG Labtech)

[0399] II. Experimental Procedure

[0400] SIK3 is a kinase that phosphorylates the substrate AMARA in the presence of ATP. The ADP-Glo ​​assay kit is a luminescent ADP detection kit used to detect changes in SIK3 enzyme activity. The kit operates in three steps: 1) AMARA, as a substrate, is phosphorylated to produce ADP in the presence of ATP; 2) After the ADP generation reaction is complete, the ADP-Glo ​​reagent is added to terminate the reaction and consume any remaining ATP; 3) The kinase detection reagent is added, converting ADP to ATP and simultaneously converting ATP into a light signal in a coupled luciferase / luciferin reaction, thereby detecting changes in enzyme activity.

[0401] The 20 mM test compound dissolved in 100% DMSO was diluted to 1 mM with 100% DMSO. This was the 100× concentration, representing the highest concentration of the compound in the reaction system. This concentration was then serially diluted 4-fold with 100% DMSO to 10 concentration points. The blank wells contained 100% DMSO. The serially diluted compound and 100% DMSO were then further diluted 20-fold in water to a 5× concentration and thoroughly mixed. 1 μL of the 5× concentration compound was added to each reaction well. 1 μL of 5% DMSO was added to the negative control well (without enzyme) and the positive control well (with enzyme and no compound). SIK3 enzyme and AMARA were diluted to a 2.5× concentration (final reaction concentration SIK3: 10 nM; AMARA: 45 μM) in reaction buffer (25 mM Tris, pH 7.5, 0.01% Triton X-100, 0.5 mM EGTA, 5 mM magnesium chloride, 2.5 mM DTT), and 2 μL of the enzyme-substrate dilution was added to the reaction system. ATP was diluted to a 2.5× concentration (final reaction concentration 5 μM) in reaction buffer, and 2 μL was added to the reaction system. The 5 μL reaction system was mixed thoroughly and incubated at room temperature for 120 min. The reaction was terminated by adding 5 μL of ADP-Glo ​​reagent, and incubated at room temperature for 40 min to consume the remaining ATP. Then, 10 μL of kinase detection reagent was added, and the system was incubated at room temperature for 30 min. The subsequent readings were used to calculate the inhibition rate using the following formula: Inhibition rate = 100 - 100 × (Test well value - Negative control value) / (Positive control value - Negative control value). Inhibition curves were plotted using Graphpad Prism software based on the compound concentrations and corresponding inhibition rates, and the concentration of the compound at which the inhibition rate reached 50%, i.e., the IC50, was calculated. 50 value.

[0402] Table 3 IC50 of the disclosed compounds on human SIK3 enzyme inhibition. 50 value

[0403] 4 17 96

[0404] Conclusion: The compound disclosed herein has a good inhibitory effect on SIK3. By comparing test example 1 and test example 3, it can be concluded that the compound disclosed herein has a selective inhibitory effect on SIK3.

[0405] Test Example 4: Inhibitory activity of the compound of the present invention on TNFα secretion in human monocytes stimulated by LPS.

[0406] I. Experimental Materials and Instruments

[0407] 1. Magnetic beads for isolating human CD14 mononuclear cells (Medini, 130-050-201)

[0408] 2. Human TNF-α enzyme-linked immunosorbent assay kit (Xinbosheng, EHC103a.96.10)

[0409] 3. DMSO (Sigma, D2650)

[0410] 4. Human peripheral mononuclear cells (Miaoshun Biotechnology, PB250F)

[0411] 5.RPMI-1640(GE Healthcare,SH30809.01)

[0412] 6. Fetal bovine serum (Gibco, 10099-141)

[0413] 7. Phosphate-buffered saline (PBS) pH 7.4 (Source Biotech, B320)

[0414] 8. Bovine serum albumin (BSA) (MP Biomedicals, 9048-46-8)

[0415] 9.EDTA(0.5M),pH 8.0(Life technology,AM9260G)

[0416] 10. Lipopolysaccharide (LPS) (Sigma, L2880)

[0417] 11. 96-hole round base plate (Corning, 3788)

[0418] 12.LS magnetic column (Miltenyi, 130-042-401)

[0419] 13. Carbon dioxide incubator (Thermo Scientific, i160)

[0420] 14. 15ml centrifuge tubes (Corning)

[0421] 15. Biosafety cabinet (Shanghai Lishen Scientific Instruments Co., Ltd., HFsafe-1200LC)

[0422] 16. High-speed refrigerated centrifuge (Thermo Scientific, ST 40R)

[0423] 17. Plate washer (Bio Tek Instruments, 405TSU)

[0424] 18. Incubator (Shanghai Yiheng Scientific Instruments Co., Ltd.)

[0425] 19. PHERAstar FS Microplate Reader (BMG Labtech)

[0426] II. Experimental Procedure

[0427] Human peripheral blood mononuclear cells secrete various cytokines in response to stimulation by pathogens (such as lipopolysaccharide). These cytokines include pro-inflammatory cytokines (such as TNFα, IL-6, and IL-β) that promote inflammatory responses, as well as cytokines that inhibit inflammatory responses or play an immunomodulatory role. This experiment used ELISA to detect the TNFα content in the culture medium of human peripheral blood mononuclear cells and to evaluate the inhibitory or promoting effects of compounds on the release of these cytokines.

[0428] Human peripheral blood mononuclear cells were cultured in RPMI 1640 medium (hereinafter referred to as complete medium) containing 10% fetal bovine serum. CD14+ mononuclear cell separation buffer was PBS solution containing 0.5% BSA and 2mM EDTA. LPS powder was dissolved in sterile water to weigh 1 mg / mL and aliquoted and stored at -20°C.

[0429] Mononuclear cell isolation and LPS treatment: Centrifuge PBMCs at 300g, 4°C for 10 min, carefully aspirate the supernatant, resuspend the cells in an appropriate volume of pre-chilled cell separation buffer, and count the cells. Adjust the cell concentration to 10^7 cells per 80 μL of separation buffer. After thoroughly and gently mixing the cells, add CD14+ cell sorting beads at a ratio of 20 μL per 10^7 cells, mix thoroughly, and incubate at 4°C for 15 minutes, shaking several times during incubation. Add pre-chilled buffer at a ratio of 2 mL per 10^7 cells, invert to mix, and centrifuge at 300g, 4°C for 10 min. While waiting for centrifugation, place the LS cell collection column on a magnetic rack, with a waste collection tube below, and add 3 mL of pre-chilled buffer to rinse the LS column. Resuspend the cell pellet at a ratio of 0.5-1 mL per 10^8 cells, and then add it to the LS column. When the cell-bound magnetic beads flow through the LS column, they are attracted by the magnetic force, while unbound cells flow out of the column. Rinse the LS column three times with 3 mL of pre-cooled buffer. Replace the cell collection tube and place it under the LS column. Add 5 mL of culture medium to the LS column. After removing the LS column from the magnetic rack, install the stopcock and steadily and evenly push the cells out of the LS column and collect them into the cell collection tube. Count the collected cells and dilute them to 6.25 × 10^6 / mL with complete culture medium. Add 160 μL of cell suspension to each well of a 96-cell round-bottom plate to achieve a total cell count of 1 × 10^5 per well. Transfer the cells to an incubator and culture for 4 hours.

[0430] The 20 mM test compound dissolved in 100% DMSO was diluted to 5 mM with 100% DMSO. This was the 500× concentration, representing the highest concentration of the compound in the reaction system. This concentration was serially diluted 4-fold with 100% DMSO to nine concentration points. Blank wells were prepared with 100% DMSO. The serially diluted compounds and 100% DMSO were then further diluted 50-fold in complete culture medium to a 10× concentration and thoroughly mixed. 20 μL of the 5× concentration compound was added to each cell culture well. 20 μL of 2% DMSO was added to the negative control wells (without LPS) and the positive control wells (with LPS and no compound). The LPS stock solution (1 mg / mL) was diluted 500-fold with complete culture medium to 2 μg / mL. 20 μL of LPS solution was added to each well to bring the final LPS concentration to 200 ng / mL, and the cells were gently shaken to mix. Cells were incubated at 37°C in a 5% CO2 incubator. After 20 hours, the supernatant was collected for ELISA experiments.

[0431] ELISA detection of TNFα secretion levels: Cytokine detection in cell culture medium was performed according to the ELISA kit instructions. Standards were dissolved in universal standard and sample diluent and diluted to the following concentrations to form a standard curve: 1000, 500, 250, 125, 62.5, 15.6, and 0 pg / mL. Samples were diluted appropriately with universal standard and sample diluent. Universal standard and sample diluent was added to blank wells, and samples or standards of different concentrations (100 μL / well) were added to the corresponding wells. The reaction wells were sealed with sealing tape and incubated at 37°C in the dark for 90 minutes. 20 minutes before use, 30× concentrated biotinylated antibody was diluted to 1× working solution with biotinylated antibody diluent. The plate was washed 5 times with 300 μL / well using a plate washer. Biotinylated antibody working solution (100 μL / well) was added to each well. The reaction wells were sealed with new sealing tape and incubated at 37°C in the dark for 60 minutes. Twenty minutes before use, dilute the 30× concentrated enzyme conjugate to 1× working solution with enzyme conjugate diluent. Wash the plate 5 times with 300 μL / well using a plate washer. Add 100 μL / well of enzyme conjugate working solution to each well. Seal the reaction wells with new sealing tape and incubate at 37°C in the dark for 30 minutes. Wash the plate 5 times with 300 μL / well using a plate washer, dry the plate, add 100 μL / well of chromogenic substrate (TMB), and incubate at 37°C in the dark for 15 minutes. Add 100 μL / well of reaction stop solution, mix well, and measure the OD450 value within 3 minutes. Calculate the inhibition rate based on the TNFα concentration per well obtained from the standard curve using the following formula: Inhibition rate = 100 - 100 × (test well value - negative control value) / (positive control value - negative control value). Inhibition curves were plotted using Graphpad Prism software based on the concentrations of the compounds and their corresponding inhibition rates. The concentration of the compound at which the inhibition rate reached 50%, i.e., the IC50 value, was then calculated. 50 value.

[0432] Table 4 shows the inhibitory activity (IC50) of the disclosed compounds on LPS-stimulated TNFα secretion in human monocytes. 50 value

[0433]

[0434]

[0435] Conclusion: The compound disclosed herein has a good inhibitory effect on LPS-stimulated TNFα secretion in human monocytes.

[0436] Test Example 5: Pharmacokinetic Evaluation

[0437] I. SD Rat Experiment

[0438] 1. Abstract

[0439] Using SD rats as test animals, the plasma drug concentrations of the disclosed compound at different time points after administration by gavage (ig) / intravenous injection (iv) in SD rats were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated to evaluate its pharmacokinetic characteristics.

[0440] 2. Test Plan

[0441] 2.1 Test Drugs

[0442] Compound 1.

[0443] 2.2 Experimental Animals

[0444] Eight SD rats, half male and half female, were randomly divided into two groups and provided by Zhejiang Vital River Laboratory Animal Technology Co., Ltd. After fasting overnight, the rats were administered the drugs via gavage and intravenous injection, respectively.

[0445] 2.3 Drug Preparation

[0446] Weigh out a certain amount of the test compound and add 5% DMSO + 5% Tween 80 + 90% physiological saline to prepare a 0.2 mg / mL colorless clear solution (gavage administration group) and a 0.2 mg / mL colorless clear solution (intravenous injection group).

[0447] 2.4 Administration

[0448] Gavage administration group: The dosage was 2.0 mg / kg, and the administration volume was 10.0 mL / kg.

[0449] Intravenous administration group: The dosage was 1.0 mg / kg, and the administration volume was 5.0 mL / kg.

[0450] 3. Operation

[0451] In the gavage administration group: 0.2 mL of blood was collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 10,000 rpm for 2 minutes (4°C), and the plasma was separated within 1 hour and stored on dry ice for later analysis. The entire process from blood collection to centrifugation was performed under ice bath conditions. Patients ate 2 hours after administration.

[0452] Intravenous injection group: Blood samples were collected before administration and at 5 minutes, 30 minutes, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours after administration, and the treatment was the same as that of the gavage group.

[0453] The content of the analyte compound in the plasma of SD rats after administration of different drug concentrations was determined: 50 μL of plasma samples from SD rats at each time point after drug administration were collected, and 25 μL of tolbutamide (2 μg / mL) was added to each sample. Proteins were precipitated with 450 μL of acetonitrile, vortexed, and centrifuged at 3700 rpm for 10 minutes. 0.5 μL of the supernatant was collected for LC / MS / MS analysis.

[0454] 4. Pharmacokinetic Parameter Results

[0455] Table 5. Pharmacokinetic parameters of the disclosed compounds in SD rats.

[0456]

[0457] Conclusion: The compound disclosed herein exhibits excellent pharmacokinetic absorption activity in SD rats and demonstrates pharmacokinetic advantages.

Claims

1. A compound of general formula (III) or a pharmaceutically acceptable salt thereof: in: X 1 Let N, X 2 For C; or, X 1 Let C and X be the values ​​of C and X respectively. 2 Let N be the number of people in the group. L represents a chemical bond or O; s is 0, 1, or 2; for W can be C, CH, or N; It can be a single bond or a double bond; R 10 It is a hydrogen atom; t is 1, 2, or 3; R 9 It is a 3- to 8-membered cycloalkyl group; R 2 It is a hydrogen atom; p is 1, 2, or 3; G 1 For CR 3 ; R 3 C 1-6 Alkoxy; R 4 and R 6 All are hydrogen atoms; n is 1; R w3 C 1-6 Halogenated alkyl groups; R y It is a hydrogen atom; and m can be 0, 1, 2, 3, or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a methoxy group.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 It is cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R w3 It is -CH2CF3.

5. The compound or its pharmaceutically usable salt according to claim 1, wherein L is a chemical bond and s is 0.

6. The compound or its pharmaceutically usable salt according to claim 1, wherein L is 0 and s is 2.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein... for or .

8. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds: , , , , , , and .

9. A compound of general formula (IIIA) or a salt thereof: in: Rings A and R 10 L, X 1 X 2 G 1 R 2 R 4 R 6 R w3 R y m, n, p, s, and t are as defined in claim 1, and the compound represented by general formula (IIIA) is not... .

10. The compound or a salt thereof according to claim 9, wherein the compound is selected from the group consisting of: , and .

11. A method for preparing a compound of general formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: A compound of general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IIB) to give a compound of general formula (III) or a pharmaceutically usable salt thereof. in: X is a halogen; Rings A, L, X 1 X 2 G 1 R 2 R 4 R 6 R 9 R 10 R w3 R y m, n, p, s, and t are as defined in claim 1.

12. The method of claim 11, wherein X is Cl.

13. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, and one or more pharmaceutically acceptable carriers or diluents.

14. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, and one or more pharmaceutically acceptable excipients.

15. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 13 or 14, in the preparation of a medicament for inhibiting SIK2.

16. Use of compound 4 according to claim 8 in the preparation of a medicament for inhibiting SIK3.

17. Use of the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 13 or 14 in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is selected from inflammatory diseases and autoimmune diseases.

18. The use according to claim 17, wherein the disease or condition is selected from rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

19. The use according to claim 18, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

Images