CN115677690A - Heteroaryl compound, preparation method and application thereof in medicine - Google Patents
Heteroaryl compound, preparation method and application thereof in medicine Download PDFInfo
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- CN115677690A CN115677690A CN202210908810.1A CN202210908810A CN115677690A CN 115677690 A CN115677690 A CN 115677690A CN 202210908810 A CN202210908810 A CN 202210908810A CN 115677690 A CN115677690 A CN 115677690A
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Abstract
The disclosure relates to heteroaryl compounds, methods of their preparation, and their use in medicine. Specifically, the disclosure relates to a heteroaryl compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound as a therapeutic agent, in particular an application of the compound as a SIK inhibitor and an application of the compound in preparing a medicament for treating and/or preventing inflammatory diseases or autoimmune diseases. Wherein each group in the general formula (I) is defined in the specification.
Description
Technical Field
The disclosure belongs to the field of medicines, and relates to a heteroaryl compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to heteroaryl compounds represented by general formula (I), a preparation method thereof, pharmaceutical compositions containing the compounds, and uses of the compounds as SIK inhibitors in preparation of drugs for treating and/or preventing inflammatory diseases or autoimmune diseases.
Background
The Salt-inducible kinase (SIK) kinases, including SIK1, SIK2 and SIK3, belong to the AMP-dependent protein kinase (AMPK) family, and these serine/threonine kinases play a key role in the regulation of cellular energy metabolism. A plurality of extracellular signals, including hormones, driver factors and the like, can further activate signal networks such as Protein Kinase A (PKA), protein Kinase C (PKC) and calcium ion-calmodulin dependent protein kinase (CaMK) by activating corresponding G protein-coupled receptor/cAMP signal pathways, and regulate various functions such as sugar metabolism, lipid metabolism, energy metabolism, cell differentiation and the like. And the SIK kinase is located at the downstream of Protein Kinase A (PKA), and the PKA directly phosphorylates the SIK kinase, increasing its binding to 14-3-3 regulatory proteins, thereby releasing and activating SIK downstream substrates, mainly comprising two classes of transcription factors, one class being CREB-regulating transcription activators (CRTCs) and the other class being histone deacetylases (HDAC 4,5,7, and 9). The released CRTCs and HDACs enter the nucleus from the cytoplasm and bind to the corresponding DNA regulatory sites to exert their transcriptional regulation. The downstream genes mainly include Pck1, G6PC which regulate metabolism and Ptgs2, IL-10, TTP and the like which are involved in inflammatory response. In addition, HDACs are also involved in the deacetylation of NF-kappa B proteins in inflammatory signaling pathways, thereby regulating the expression of inflammatory factors regulated by NF-kappa B.
Recent studies have shown that SIK kinase plays a crucial role in the immune response of innate immune cells, particularly macrophages and dendritic cells. Innate immune cells have a complex and multifaceted mechanism of action in the immune response. After infection or tissue injury, macrophages can show a phenotype (M1 type) promoting inflammatory progression on one hand, and secrete a large amount of proinflammatory factors including TNFa and IL-12 to start the innate immunity and the secondary immunity system of the body, so as to achieve the purpose of eliminating microbial infection and other immunogens. On the other hand, macrophages also play a role in immune regulation, and can be classified into immunoregulation type macrophages (M2 type) to secrete inflammation inhibitory factors such as IL-10 and IL-1ra and the like so as to ensure the control and timely elimination of inflammatory response. M1-type macrophages that contribute to inflammation are closely associated with autoimmune diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. While M2 type, which regulates the inflammatory response, is effective in inhibiting the development of inflammation. In addition, IL-10 knockout mice display a phenotype associated with inflammatory bowel disease and IL-10 gene deficiency is associated with the development of inflammatory bowel disease in humans. SIK kinase can inhibit the expression of IL-10 by regulating CREB transcription factor; by modulating HDAC and NFkB pathways, expression of TNFa is promoted, biasing macrophages towards the M1 phenotype. Thus, inhibition of SIK activity promotes differentiation of innate immune cells to the M2-resistant type, decreases proinflammatory factors such as TNFa, and increases the inflammatory suppressor IL-10. Thus, promoting macrophage differentiation to an immune-tolerant type by inhibiting SIK kinase activity provides a novel therapeutic mechanism for autoimmune diseases.
There are three subtypes of SIK kinases known to date, SIK1, SIK2 and SIK3. The research result of a mouse gene knockout model finds that SIK2 and SIK3 play more important roles in promoting macrophage differentiation. SIK1 is mainly involved in salt metabolism, and SIK1 knockout mice are more sensitive to high-salt-induced blood pressure elevation. The phenotype of the SIK2 knockout mouse is basically normal, and plasma triglycerides are increased to a certain extent; whereas SIK3 knockout mice have a smaller body weight suggesting a correlation with early skeletal development. Although there is currently no sufficient research result if the inhibition of SIK kinase by small molecule compounds is consistent with the phenotype of mouse gene knock-out, the selective targeting of SIK2/SIK3 by small molecule kinase inhibitors of SIK developed against autoimmune diseases, while circumventing the inhibitory effect on SIK1, is a safer and effective development strategy.
Among the currently disclosed SIK2/SIK3 inhibitors are WO2018188785A1, WO2018193084A1, WO2019198940A1, WO2019202160A1, WO2019238424A1, WO2020083926A1, WO2020239658A1, WO2019105886A1 and WO2020239660A1.
Disclosure of Invention
The object of the present disclosure is to provide a compound represented by the general formula (I):
wherein:
X 1 is N, X 2 Is C; or, X 1 Is C, X 2 Is N;
R 1 is-L- (CR) 7 R 8 ) s -A-B；
L is selected from the group consisting of a bond, O, and S;
a is heterocyclyl, wherein said heterocyclyl is optionally selected from halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -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) 2 R J1 、-S(O) 2 NR g1 R h1 Aryl and heteroaryl, substituted with one or more substituents;
b is selected from-C (O) R 9 ；
R 9 Selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -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) 2 R J2 、-S(O) 2 NR g2 R h2 Aryl and heteroaryl, substituted with one or more substituents;
R 7 and R 8 The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, cyano, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, and cycloalkyl;
G 1 is CR 3 Or an N atom;
R 2 、R 3 、R 4 and R 6 The same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more halogen atoms or halogen atomsEach aryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 5 selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy and-NR 5a R 5b Wherein said alkenyl, alkynyl, alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 5a and R 5b The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;
R w is-NR w1 R w2 or-NR w3 -；
R w1 Selected from the group consisting of alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R w2 and R w3 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
when R is w is-NR w3 When the N atom is not in contact with R 5 Together forming a heterocyclyl group, said heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R f1 and R f2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R g1 、R h1 、R g2 and R h2 Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkenyl groups, alkynyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or R g1 And R h1 To the bound N atom, R g2 And R h2 Together with the attached N atom, form a heterocyclyl group, said heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R J1 and R J2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl groupAlkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
p is 1,2 or 3;
s is 0, 1,2,3 or 4.
In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 And R 8 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III):
wherein:
ring a is a 3-to 12-membered heterocyclic group containing at least one nitrogen atom;
R 10 the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, amino, aryl, and heteroaryl;
R y the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
t is 1,2 or 3;
n is 0, 1 or 2;
m is 0, 1,2,3 or 4;
L、X 1 、X 2 、G 1 、R 2 、R 4 、R 6 、R 9 、R w3 p and s are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein
Is composed of
R 2 And p is as defined in formula (I); more preferably, the amount of the organic solvent is,
is composed of
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III) or a pharmaceutically acceptable salt thereof, wherein R is 2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, R 2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 A haloalkoxy group; more preferably, R 2 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III) or a pharmaceutically acceptable salt thereof, wherein G 1 Is CR 3 ；R 3 As defined in formula (I); preferably, R 3 Selected from hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 A haloalkoxy group; further preferably, R 3 Is C 1-6 Alkoxy or C 1-6 A haloalkoxy group; more preferably, R 3 Is C 1-6 An alkoxy group; most preferablyEarth, R 3 Is methoxy.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III) or a pharmaceutically acceptable salt thereof, wherein R is 4 And R 6 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; preferably, R 4 And R 6 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl and C 1-6 A haloalkyl group; more preferably, R 4 And R 6 Are all hydrogen atoms.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III) or a pharmaceutically acceptable salt thereof, wherein R is 9 Is a 3-to 8-membered cycloalkyl group or a 3-to 12-membered heterocyclyl group, wherein said 3-to 8-membered cycloalkyl group and said 3-to 12-membered heterocyclyl group are each independently optionally selected from halogen, C 2-6 Alkenyl radical, C 2-6 Alkynyl, cyano, nitro, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, oxo, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 3-to 8-membered cycloalkyloxy and 3-to 12-membered heteroalkyloxy.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (III) or a pharmaceutically acceptable salt thereof, wherein R is 9 Is a 3-to 8-membered cycloalkyl group or a 3-to 12-membered heterocyclyl group, wherein said 3-to 8-membered cycloalkyl group and said 3-to 12-membered heterocyclyl group are each independently optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy and oxo.
In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I) and the general formula (III)Or a pharmaceutically acceptable salt thereof, wherein R 9 Is a 3 to 8 membered cycloalkyl group, wherein said 3 to 8 membered cycloalkyl group is optionally selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy and oxo; preferably, R 9 Is a 3 to 8 membered cycloalkyl group; more preferably, R 9 Is cyclopropyl.
In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 10 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 A haloalkoxy group; preferably, R 10 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen atom, halogen, cyano, nitro, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy and-NR 5a R 5b Wherein said C 1-6 Alkyl and C 1-6 Alkoxy is independently selected from halogen, cyano, nitro, hydroxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; r 5a And R 5b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 A hydroxyalkyl group;
preferably, R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy and C 1-6 A haloalkoxy group;
more preferably, R 5 Is C 1-6 Alkoxy or C 1-6 A haloalkoxy group.
In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R w1 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl and 3 to 8-membered cycloalkyl, wherein said C 1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo; and/or, R w2 Selected from hydrogen atom, C 1-6 Alkyl radical, C 1-6 Haloalkyl and 3 to 8-membered cycloalkyl, wherein said C is 1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl and oxo;
preferably, R w1 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl and 3 to 8-membered cycloalkyl, wherein said C is 1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens; and/or, R w2 Selected from hydrogen atom, C 1-6 Alkyl radical, C 1-6 Haloalkyl and 3 to 8-membered cycloalkyl, wherein said C is 1-6 Alkyl and 3 to 8 membered cycloalkyl each independently optionally substituted with one or more halogens;
more preferably, R w1 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl and 3 to 8-membered cycloalkyl; and/or, R w2 Is a hydrogen atom;
more preferably, R w1 Is cyclopropyl; and/or, R w2 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III), or a pharmaceutically acceptable salt thereof, wherein R is w3 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl and 3 to 8-membered cycloalkyl, wherein said C is 1-6 Alkyl and 3 to 8 membered cycloalkyl are each independently optionally selected from halogen, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, amino, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl;
preferably, R w3 Is C 1-6 A haloalkyl group;
more preferably, R w3 is-CH 2 CF 3 。
In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein n is 1.
In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein m is 0.
In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R y Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy and amino;
preferably, R y Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group;
more preferably, R y Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III) or a pharmaceutically acceptable salt thereof, wherein s is 0, 1 or 2.
In some preferred embodiments of the present disclosure, the compound represented by formula (I) or formula (III) or a pharmaceutically acceptable salt thereof, wherein L is a bond or O.
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III) or a pharmaceutically acceptable salt thereof, wherein L is a bond; and/or s is 0.
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III) or a pharmaceutically acceptable salt thereof, wherein L is O or S; and/or, s is 1 or 2;
preferably, L is O; and/or s is 2.
In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (III) or a pharmaceutically acceptable salt thereof, wherein p is 1.
In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 1.
In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein
Is composed of
W is C, CH or N;
is a single or double bond; r 10 And t is as defined in formula (III);
preferably, the first and second electrodes are formed of a metal,
is composed of
R 10 And t is as defined in formula (III);
more preferably, the amount of the organic solvent is,
is composed of
In some preferred embodiments of the present disclosure, the compound represented by the formula (III)A compound or a pharmaceutically acceptable salt thereof, wherein X 1 Is C, X 2 Is N; or, X 1 Is N, X 2 Is C; l is selected from the group consisting of a bond, O and S; ring a is a 3-to 12-membered heterocyclic group containing at least one nitrogen atom; r 2 Is a hydrogen atom; g 1 Is CR 3 ；R 3 Is C 1-6 An alkoxy group; r 4 And R 6 Are each a hydrogen atom; r 10 Is a hydrogen atom; r is 9 Is a 3-to 8-membered cycloalkyl group or a 3-to 12-membered heterocyclyl group, wherein said 3-to 8-membered cycloalkyl group and said 3-to 12-membered heterocyclyl group are each independently optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy and oxo; r is w3 Is C 1-6 A haloalkyl group; s is 0, 1 or 2; n is 1; r y Is a hydrogen atom; t is 1.
In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein
Is composed of
Is composed of
R 4 And R 6 Are each a hydrogen atom; r 9 Is a 3 to 8 membered cycloalkyl group; s is 0, 1 or 2; l is a bond or O; g 1 Is CR 3 ；R 3 Is C 1-6 An alkoxy group; r w3 Is C 1-6 A haloalkyl group; n is 1; m is 0.
Table a typical compounds of the present disclosure include, but are not limited to:
further, the present disclosure provides a compound represented by general formula (IIIA):
wherein:
R 10 is a hydrogen atom;
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 formula (III).
Table B typical intermediate compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising:
nucleophilic substitution reaction is carried out between the compound shown in the general formula (IIIA) or the salt thereof and the compound shown in the general formula (IIB) or the salt thereof to obtain the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Cl;
ring 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 formula (III).
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (III) or table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The disclosure further relates to the use of a compound of formula (I), formula (III) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting SIK2 and/or SIK3.
The present disclosure further relates to the use of a compound of formula (I), formula (III) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder selected from inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with excessive secretion of TNF α, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and diseases associated with abnormal angiogenesis; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease; more preferably, wherein said inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous Lupus Erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.
The present disclosure further relates to a method of inhibiting SIK2 and/or SIK3 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (III) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure further relates to a method of treating and/or preventing a disease or disorder selected from the group consisting of inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with excessive secretion of TNF α, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases and diseases associated with abnormal angiogenesis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (III) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease; more preferably, wherein said inflammatory disease or autoimmune disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous Lupus Erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.
The present disclosure further relates to compounds of formula (I), formula (III) and table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.
The disclosure further relates to a compound of formula (I), formula (III) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting SIK2 and/or SIK3.
The present disclosure further relates to a compound of formula (I), formula (III) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder selected from the group consisting of inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with excessive secretion of TNF α, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases and diseases associated with abnormal angiogenesis; preferably, wherein said disease or condition is an inflammatory disease or an autoimmune disease; more preferably, wherein said inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous Lupus Erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.
The disease or disorder is preferably a SIK2 and/or SIK3 mediated disease or disorder.
The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
As a general guide, the active compound is preferably administered in a unit dose, or in a manner such that the patient can self-administer the compound in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. Suitable unit doses may be from 0.1 to 1000mg.
The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickening agent. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model Deltec CADD-PLUS. TM. 5400.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be used to prepare injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Description of the terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group containing 1 to 12 (e.g., 1,2,3,4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms 1-12 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) 1-6 Alkyl groups). <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- </xnotran>Hexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched chain isomers thereof, and the like. The alkyl group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally one or more substituents selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups (i.e., C) containing 2 to 12 (e.g., 2,3,4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred 2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups (i.e., C) containing 2 to 12 (e.g., 2,3,4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred 2-12 Alkynyl), more preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms (i.e., 3 to 20 membered cycloalkyl groups), preferably 3 to 14 (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (i.e., 3 to 14 membered cycloalkyl groups), preferably 3 to 8 (e.g., 3,4, 5, 6, 7 and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds (i.e., a 5 to 20 membered spirocycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds (i.e., a 5 to 20 membered fused cyclic alkyl). Preferably 6 to 14 (i.e. 6 to 14 fused cycloalkyl) members, more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 fused cycloalkyl) members. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused ring alkyls. Non-limiting examples of fused ring alkyl groups include:
the term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 member bridged cycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered bridged cycloalkyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring includes a cycloalkyl ring (including monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the rings attached together with the parent structure are cycloalkyl, non-limiting examples of which include
Etc.; preferably, it is
Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon (i.e., a 3-to 20-membered heterocyclyl). Preferably 3 to 12 (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3,4, 5, 6, 7 and 8), of which 1-3 (e.g., 1,2 and 3) are heteroatoms (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. Which may contain one or more double bonds (i.e., 5 to 20 membered spiroheterocyclyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spiroheterocyclyl). The spiro heterocyclic group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5 to 20 membered fused heterocyclyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered fused heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, and are preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5 to 14 membered bridged heterocyclyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered bridged heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
the heterocyclyl ring includes heterocyclyl groups (including monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl groups) as described above fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
The heterocyclyl group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group (i.e., a 6 to 14 membered aryl group) having a conjugated pi-electron system, preferably 6 to 10 membered (e.g., 6, 7, 8, 9 or 10 membered) (i.e., 6 to 10 membered aryl), such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1,2,3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen (i.e., a 5-to 14-membered heteroaryl). Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from the parent ring atom by removal of one hydrogen atom, or residues derived from the parent ring atom by removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".
The term "amino protecting group" is a group that is easily removed by introduction in order to keep the amino group unchanged when the reaction is carried out at other sites of the molecule. Non-limiting examples include, but are not limited to, (trimethylsilane) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro.
The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
The term "heterocyclyloxy" refers to the heterocyclyl-O-, wherein heterocyclyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to-OH.
The term "amino" refers to the group-NH 2 。
The term "cyano" refers to — CN.
The term "nitro" means-NO 2 。
The term "oxo" or "oxo" means "= O".
The term "carbonyl" refers to C = O.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.
"Boc" refers to t-butyloxycarbonyl.
The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in a substituent in a compound of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.
In the chemical structure of the compounds described in this disclosure, a bond
Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure
Can be made of
Or at the same time comprise
And
two configurations. For all carbon-carbon double bonds, both Z-and E-forms are included, even if only one configuration is named.
The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. Examples of lactam-lactam equilibria are shown below:
when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:
all tautomeric forms are within the scope of the disclosure, and the designation of compounds does not exclude any tautomers.
The compounds of the present disclosure include all suitable isotopic derivatives of the compounds 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 can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, respectively 2 H (deuterium, D), 3 H (tritium, T), 11 C、 13 C、 14 C、 15 N、 17 O、 18 O、 32 p、 33 p、 33 S、 34 S、 35 S、 36 S、 18 F、 36 Cl、 82 Br、 123 I、 124 I、 125 I、 129 I and 131 i, etc., preferably deuterium.
Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, where replacement of deuterium may be partial or complete, and replacement of partial deuterium means replacement of at least one hydrogen by at least one deuterium.
When a position is specifically designated as deuterium, D, the position is understood to be deuterium with an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compound of examples may have a natural abundance of deuterium greater than deuterium of at least 1000 times an abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times an abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times an abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times an abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times an abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times an abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times an abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times an abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times an abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times an abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times an abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times an abundance of deuterium (i.97% of deuterium), at least 99% abundance of deuterium (i.99.99.99.99% deuterium incorporation of deuterium, or at least 6633.3.99% of deuterium incorporation of deuterium. "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of drug or agent sufficient to achieve or partially achieve the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.
The term "inflammatory disorder" is meant to include the following diseases or disorders: rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway diseases (e.g., asthma, rhinitis), chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel diseases (e.g., crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., bypass postoperative complications or chronic endotoxin conditions contributing to, for example, chronic heart failure) and related diseases involving cartilage such as articular cartilage. Preferably, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g. asthma), chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease. More preferably, the term refers to rheumatoid arthritis, chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease.
The term "autoimmune disease" is meant to include the following diseases or conditions: obstructive airway diseases, including conditions such as COPD, asthma (e.g. intrinsic asthma, extrinsic asthma, dust asthma, asthma infancy), in particular chronic or refractory asthma (e.g. late asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic Lupus Erythematosus (SLE), cutaneous Lupus Erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease (e.g. autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis), sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (hashimoto and autoimmune thyroiditis), contact dermatitis, inflammatory bowel disease (e.g. crohn's disease and ulcerative colitis), sjogren's syndrome and amyotrophic lateral sclerosis. Preferably, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes and inflammatory bowel disease.
The term "disease involving impairment of cartilage turnover" includes the following diseases or conditions: osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful dystrophy, tietz syndrome or costal chondritis, fibromyalgia, osteochondral spondylitis, neurogenic or neurogenic arthritis, arthropathies, endemic arthritis such as endemic osteoarthritis, melenib's (Mseleni) disease, and hanguddu's disease); degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.
The term "diseases involving impairment of bone turnover" includes the following diseases or conditions: osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticoid-induced osteoporosis, and juvenile osteoporosis), osteoporosis through neoplastic bone marrow disorders, osteopenia, hormone deficiency (vitamin D deficiency, male and female hypogonadism), hormone excess (hyperprolactinemia, excess glucocorticoid, hyperthyroidism, hyperparathyroidism), paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, hypophosphatasia.
The term "diseases associated with excessive secretion of TNF, interferon, IL-12 and/or IL-23" includes conditions such as: systemic Lupus Erythematosus (SLE) and Cutaneous Lupus Erythematosus (CLE), lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn's disease.
The term "respiratory disease" refers to a disease that affects organs involved in breathing, such as the nose, pharynx, larynx, eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., septum and intercostal) and nerves. Preferably, examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocarbonic acid hyperventilation (isocapanic hyperventilation), childhood asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema), pulmonary hypertension, interstitial pulmonary fibrosis and/or airway inflammation, cystic fibrosis and hypoxia.
The term "proliferative disease" refers to conditions such as: cancer, myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis), and fibrosis. Preferably, the term refers to cancer.
The term "cancer" includes leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, dysplastic neuroepithelial tumors of embryos, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastoma, neuroblastoma, germ cell tumors, teratomas, gastric cancer, esophageal cancer, liver cancer, cholangiocellular cancer, 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, vulval cancer, bladder cancer, renal cancer, squamous cell carcinoma, sarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, ewing's sarcoma, gastrointestinal stromal tumors (GIST), kaposi's sarcoma, and pediatric cancer. The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
Synthesis of the Compounds of the disclosure
In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
scheme one
The invention discloses a preparation method of a compound shown in a general formula (III) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
(a) Removing the amino protecting group of the compound shown in the general formula (IIIC) or the salt thereof under an acidic condition to obtain a compound shown in the general formula (IIIA) or the salt thereof,
(b) Nucleophilic substitution reaction is carried out on the compound shown in the general formula (IIIA) or salt thereof and the compound shown in the general formula (IIB) or salt thereof under the action of alkali to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof,
wherein:
m is an amino protecting group, preferably Boc;
x is halogen; preferably Cl;
ring 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 formula (III).
In the above reaction of step (a), the reagents providing acidic conditions include organic acids including, but not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, me, and inorganic acids 3 SiCl and TMSOTf; such inorganic acids include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Preferably, the agent that provides acidic conditions is a1, 4-dioxane solution of hydrogen chloride.
In the reaction of the above step (b), the reagent for providing basic conditions includes organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate (potassium acetate), sodium tert-butoxide, potassium tert-butoxide or 1, 8-diazabicycloundecen-7-ene, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide. Preferably, the reagent that provides basic conditions is triethylamine.
The reactions of steps (a) and (b) above are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and a mixture thereof, preferably dichloromethane.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 The units in (ppm) are given. NMR was measured using Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: agilent, MS model: 6110/6120Quadrupole MS).
waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)
THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active)
High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC1200 DAD, agilent HPLC1200VWD and Waters HPLC e2695-2489.
Chiral HPLC analytical determination Agilent 1260DAD HPLC was used.
High performance liquid preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP, and Gilson GX-281.
Chiral preparation a Shimadzu LC-20AP preparative chromatograph was used.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).
The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.
Average inhibition rate of kinase and IC 50 The values were determined with a NovoStar microplate reader (BMG, germany).
Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenator.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.
In the examples, the solution means an aqueous solution without specific indication.
In the examples, the reaction temperature is, unless otherwise specified, room temperature and is 20 ℃ to 30 ℃.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: in the n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can also be added for adjustment.
Example 1
6- (6- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) ethoxy) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1
First step of
6- (6-Bromopyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1c
6-bromo-3-iodopyrazolo [1,5-a ] pyridine 1a (2g, 6.19mmol, prepared as disclosed in intermediate 15 on page 145 of the specification in patent application WO2019105886A 1), 8-methoxy-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborocan-2-yl) -2- (2,2,2-trifluoroethyl) -3,4-dihydroisoquinolin-1 (2H) -one 1b (2.9g, 7.52mmol, prepared as disclosed in intermediate 14 on page 70 of the specification in patent application WO2020239660A 1), cesium carbonate (6g, 18.42mmol), 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (450mg, 0.62mmol) were suspended in 120mL of a mixed solution of 1,4-dioxane and water (V: V = 5), heated under nitrogen protection for 8 hours, and stirred at 90 ℃. After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1c (2.4 g, yield: 85.3%).
MS m/z(ESI):456.0[M+2]。
Second step of
8-methoxy-6- (6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1- (2H) -one 1d
(3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyrazolo [1,5-a ] pyridin-6-yl) boronic acid 1e
Compound 1c (280mg, 0.62mmol), pinacol diboron (188mg, 0.74mmol), potassium acetate (182mg, 1.85mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (45mg, 0.06mmol) was heated to 100 ℃ under nitrogen and stirred for 16 hours. After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system a to give a mixture of the title compounds 1d and 1e (300 mg).
1d MS m/z(ESI):502.1[M+1]。
1e MS m/z(ESI):420.2[M+1]。
The third step
6- (6-Hydroxypyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1f
A mixture (300 mg) of compounds 1d and 1e was dissolved in tetrahydrofuran (20 mL), and hydrogen peroxide (204mg, 1.79mmol,30% by volume) was added dropwise under ice-bath, followed by stirring for 10 minutes, followed by addition of sodium hydroxide solution (0.3M, 2mL) and stirring at room temperature for 2 hours. After quenching with water (10 mL), extraction with ethyl acetate (20 mL. Times.3), drying over anhydrous sodium sulfate, removal of the drying agent by filtration, and concentration of the filtrate under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1f (200 mg, yield: 85.3%).
MS m/z(ESI):392.1[M+1]。
The fourth step
4- (2- ((3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethyl) piperazine-1-carboxylic acid tert-butyl ester 1h
Compound 1f (200mg, 0.51mmol), tert-butyl 4- (2-bromoethyl) piperazine-1-carboxylate 1g (165mg, 0.56mmol, shaoyuan chemical technology (Shanghai) Co., ltd.), cesium carbonate (333mg, 1.02mmol) was suspended in N, N-dimethylformamide (5 mL), and stirred at 80 ℃ for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1h (300 mg, yield: 97.2%).
MS m/z(ESI):604.2[M+1]。
The fifth step
8-methoxy-6- (6- (2- (piperazin-1-yl) ethoxy) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one hydrochloride 1i
Compound 1h (300mg, 0.49mmol) was dissolved in 2mL of dichloromethane, and a1, 4-dioxane solution (4M, 5 mL) of hydrogen chloride was added thereto, followed by stirring at room temperature for 1 hour. Concentration under reduced pressure gave the title compound 1i (268 mg, yield: 99.8%) which was directly subjected to the next reaction without purification.
MS m/z(ESI):504.1[M+1]。
The sixth step
6- (6- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) ethoxy) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1
Compound 1i (268mg, 0.49mmol, hydrochloride salt) was suspended in 20mL of dichloromethane, triethylamine (151mg, 1.49mmol) was added, cyclopropylcarbonyl chloride 1j (78mg, 0.74mmol, afahesa (China) chemical Co., ltd.) was added, the reaction was stirred at room temperature for 1 hour, and the reaction was purified by high performance liquid chromatography (column: sharpSil-T Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L of ammonium hydrogencarbonate); mobile phase 2: acetonitrile; gradient: 30% -50%, flow rate: 30 mL/min) to give the title product 1 (70 mg, yield: 24.6%). MS m/z (ESI) 572.2[ 2 ] M +1].
1 H NMR(500MHz,CD 3 OD)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),3.83(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)。
Example 2
6- (6- (1- (cyclopropylcarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 2
First step of
4- (3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyrazolo [1,5-a ] pyridin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 2b
Compound 1c (300mg, 0.66mmol), tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate 2a (2454mg, 0.79mmol, yaoshima chemical technology (shanghai) co.), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (48mg, 0.06mmol), anhydrous potassium carbonate (183mg, 1.32mmol) was suspended in a mixed solution of 1, 4-dioxane and water (V: V =5, 1, 25 mL), and stirred at 100 ℃ for 8 hours under nitrogen protection. Cooled to room temperature, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 2b (370 mg, yield: 100%).
MS m/z(ESI):557.1[M+1]。
Second step of
8-methoxy-6- (6- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one hydrochloride 2c
Compound 2b (100mg, 0.17mmol) was dissolved in 2mL of dichloromethane, and a solution of hydrogen chloride in 1, 4-dioxane (4M, 5mL) was added thereto, followed by stirring at room temperature for 1 hour. Concentration under reduced pressure gave the title compound 2c (88 mg, yield: 99.3%). The product was directly subjected to the next reaction without purification.
MS m/z(ESI):457.1[M+1]。
The third step
6- (6- (1- (cyclopropylcarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 2
Compound 2C (40mg, 0.08mmol, hydrochloride salt) was dissolved in 20mL of dichloromethane, triethylamine (27mg, 0.26mmol) was added, cyclopropylcarbonyl chloride 1i (13mg, 0.124mmol) was added, stirring was carried out at room temperature for 1 hour, and purification was carried out by high performance liquid chromatography (column: sharpSil-T Prep C18 150. Mu.m, 5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; gradient: 35% -55%, flow rate: 30 mL/min) to give the title product 2 (25 mg, yield: 54.3%).
MS m/z(ESI):525.2[M+1]。
1 H NMR(500MHz,DMSO-d 6 )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),4.18(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)。
Example 3
6- (7- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) ethoxy) imidazo [1,2-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 3
First step of
6- (7-Fluoroimidazo [1,2-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 3c
The compound 7-fluoroimidazo [1,2-a ] pyridine 3a (350mg, 2.57mmol, available from Shanghai Biao pharmaceutical science Co., ltd.) was dissolved in N, N-dimethylacetamide (10 mL), and 6-bromo-8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 3b (870mg, 2.57mmol, prepared by the method disclosed in intermediate 39 on page 162 of the specification in patent application WO2019238424A 1), potassium acetate (631mg, 6.43mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (180mg, 0.25mmol) were added, and stirred at 120 ℃ under nitrogen for 3 hours. After cooling to room temperature and concentration 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%).
MS m/z(ESI):394.1[M+1]。
Second step of
4- (2- ((3- (8-methoxy-1-oxo-2- (2, 2-trifluoroethyl) -1,2,3, 4-tetrahydroisoquinolin) -6-yl) imidazo [1,2-a ] pyridin-7-yl) oxy) ethyl) piperazine-1-carboxylic acid tert-butyl ester 3e
Tert-butyl 4- (2-hydroxyethyl) piperazine-1-carboxylate 3d (1.60g, 6.95mmol, haohnhong biomedical science Co., ltd., shanghai) was dissolved in 15mL of N, N-dimethylformamide, and sodium hydride (270mg, 7.05mmol, haohio biomedical science Co., ltd., shanghai) was added in portions, and the reaction was stirred at room temperature for 30 minutes, followed by addition of compound 3c (450mg, 1.14mmol), and stirring at room temperature for 2 hours. Quenched by addition of 20mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, 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%).
MS m/z(ESI):604.2[M+1]。
The third step
8-methoxy-6- (7- (2- (piperazin-1-yl) ethoxy) imidazo [1,2-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 3f
Compound 3e (0.65g, 1.1 mmol) was dissolved in 15mL of methylene chloride, and a solution of hydrogen chloride in 1, 4-dioxane (4M, 2.7 mL) was added thereto, followed by stirring at room temperature for 3 hours. Concentration under reduced pressure gave the title compound 3f (500 mg, yield: 92.2%) which was used in the next step without purification.
MS m/z(ESI):504.2[M+1]。
The fourth step
6- (7- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) ethoxy) imidazo [1,2-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 3
Compound 3f (500mg, 0.87mmol) was dissolved in 20mL of dichloromethane, triethylamine (890mg, 8.8mmol) was added, compound 1j (181mg, 1.73mmol) was added, the reaction was stirred at room temperature for 10 minutes, and purified by high performance liquid chromatography (column: sharpSil-T Prep C18. Multidot.30mm, 5 μm; mobile phase 1: water (containing 10mmol/L of ammonium hydrogencarbonate), mobile phase 2: acetonitrile; gradient: 32% -52%, flow rate: 30 mL/min) to give the title product 3 (230 mg, yield: 46.4%).
MS m/z(ESI):572.3[M+1]。
1 H NMR(500MHz,DMSO-d 6 )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)。
Example 4
8-methoxy-6- (6- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4
First step of
8-methoxy-6- (6- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 4
Compound 2c (50mg, 0.1mmol) was dissolved in methanol (5 mL), glacial acetic acid (18mg, 0.3mmol), anhydrous sodium acetate (33mg, 0.4mmol) and 37% aqueous formaldehyde (26mg, 0.3mmol) were added, and the reaction was stirred at room temperature for 30 minutes, followed by addition of sodium cyanoborohydride (12mg, 0.2mmol), and stirring at room temperature for 1 hour. Purification by high performance liquid chromatography (column: sharpSil-T Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 12 min gradient, acetonitrile phase 44% -56%, flow rate: 30 mL/min) afforded the title product 4 (24 mg, yield: 50.0%).
MS m/z(ESI):471.7[M+1]。
1 H NMR(500MHz,DMSO-d 6 )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),4.34(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)。
Example 5
6- (6- (1-ethyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 5
First step of
6- (6- (1-Ethyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 5
Compound 2c (80mg, 0.16mmol) was dissolved in N, N-dimethylformamide (5 mL), and cesium carbonate (106mg, 0.3mmol) and iodoethane (31mg, 0.2mmol) were added, and the reaction was stirred at room temperature for 5 hours. Purification by high performance liquid chromatography (column: sharpSil-T Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient, acetonitrile phase 45% -65%, flow rate: 30 mL/min) afforded the title product 5 (30 mg, yield: 38%).
MS m/z(ESI):485.8[M+1]。
1 H NMR(500MHz,CD 3 OD)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)。
Example 6
8-methoxy-6- (6- (1-propyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 6
First step of
8-methoxy-6- (6- (1-propyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 6
Compound 2c (100mg, 0.22mmol) was dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (286mg, 0.88mmol) and 1-iodopropane (56mg, 0.33mmol) were added, and the reaction was stirred at 50 ℃ for 2 hours. Purification by high performance liquid chromatography (column: YMC Triart-Exrs Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 48% -63%, flow rate: 30 mL/min) afforded the title product 6 (40 mg, yield: 36.6%). MS m/z (ESI) 499.8[ deg.C ] M +1].
1 H NMR(500MHz,DMSO-d 6 )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)。
Example 7
6- (6- (1-isopropyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 7
First step of
6- (6- (1-isopropyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 7
Compound 2c (100mg, 0.22mmol) was dissolved in N, N-dimethylformamide (5 mL), and cesium carbonate (286mg, 0.88mmol) and 2-iodopropane (56mg, 0.33mmol) were added, followed by stirring at 80 ℃ for 5 hours. Purification by high performance liquid chromatography (column: sharpSil-T Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 20 min gradient, acetonitrile phase 40% -60%, flow rate: 30 mL/min) afforded the title product 7 (45 mg, yield: 44.5%).
MS m/z(ESI):499.2[M+1]。
1 H NMR(500MHz,DMSO-d 6 )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,2H),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)。
Example 8
6- (6- (1- (cyclopropylmethyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 8
First step of
6- (6- (1- (cyclopropylmethyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-3-yl) -8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 8
Compound 2c (100mg, 0.22mmol) was dissolved in methanol (5 mL), glacial acetic acid (37mg, 0.62mmol), anhydrous sodium acetate (34mg, 0.42mmol), and cyclopropanecarboxaldehyde (22mg, 0.3mmol) were added, and the reaction was stirred at room temperature for 30 minutes, followed by addition of sodium cyanoborohydride (25mg, 0.42mmol), and stirring at room temperature for 30 hours. Purification by high performance liquid chromatography (column: YMC Triart-Exrs Prep C18 x 30mm,5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate), mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 47% -62%, flow rate: 30 mL/min) afforded the title product 8 (40 mg, yield: 38.6%). MS m/z (ESI) 511.8[ 2 ] M +1].
1 H NMR(500MHz,DMSO-d 6 )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)。
Biological evaluation
The present disclosure is further described below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.
Test example 1 inhibition of human SIK1 kinase by Compounds of the disclosure
Experimental materials and instruments
SIK1 enzyme (Carna, 02-131)
2.AMARA(GL,226536)
3.DMSO(Sigma,D2650)
4.96-well plate (Corning, 3365)
5.384-well plate (Corning, 3573)
6. Staurosporine (MCE HY-15141)
7.ATP(Sigma,2383-5g)
8. Magnesium chloride (Sigma, M2670-500 g)
9.DTT(Sigma，D0632-10g)
10.Triton X-100(Sigma，T9284-100 mL)
11.HEPES(Gibco，11344-041)
Brij-35 solution (Sigma, B4184-100 mL)
13.EDTA(Gibco，15575-038)
14. Coating Reagent #3 (Coating Reagent #3, perkin Elmer)
15.Caliper EZ Reader No.2(Perkin Elmer)
Precision automatic liquid-transfering system (BioTek)
17. Constant temperature box (Shanghai Boxun)
Second, experimental procedure
SIK1 is a kinase that phosphorylates the substrate AMARA in the presence of ATP. Mobility shift assay (Mobility shift assay) can be used to detect changes in SIK1 enzyme activity. Using FAM fluorescently labeled AMARA as a substrate, AMARA is phosphorylated in the presence of ATP and then carries a phosphate group, which differs by 3 negative charges from the non-phosphorylated substrate. And (3) sucking the reacted liquid into a microfluidic chip, and allowing the AMARA substrate and the product to enter a capillary with an electric field and perform electrophoresis towards the positive electrode. Because the polypeptide product carries phosphate ions and has a high migration rate, the residual substrate and the product are separated in the mode, and finally the peak value ratio of the product to the residual substrate is calculated by using a fluorescence detection system, so that the change of the enzyme activity is detected.
Diluting 20mM test compound dissolved in 100% DMSO to 500. Mu.M, which is a concentration 50 times the highest concentration point of the compound in the reaction system, with 100% DMSO to dilute the compound at this concentration 4 times, with 9 concentration points, 10 concentration points in total, blank wells are 100% DMSO. The above serially diluted compounds and 100% DMSO in 1Xkinase buffer (50mM HEPES, pH7.5, 10mM MgCl) 2 2mM DTT,0.01% Triton X-100) to a concentration of 5X, and mixing well; mu.L of 5 Xconcentration compound was taken in the reaction wells, and 5. Mu.L of 10% DMSO was added to the negative control wells (no enzyme added) and the positive control wells (no compound added with enzyme). The SIK1 enzyme was diluted to 2.5-fold concentration (final reaction concentration 18 nM) in 1 Xkinase buffer, and 10. Mu.L of the enzyme dilution was transferred to the reaction system and incubated at room temperature for 10 minutes. AMARA and ATP were diluted to a 2.5-fold concentration (AMARA reaction final concentration of 3. Mu.M, ATP reaction final concentration of 128. Mu.M) in 1 Xkinase buffer, 10. Mu.L of the substrate and ATP solution were transferred to the reaction system, mixed well, reacted at 28 ℃ for 60 minutes, and 25. Mu.L of a stop solution (100 mM HEPES, pH7.5, 0.015% Brij-35,0.2% coating reagent #3, 50mM EDTA) was added.
Reading the reaction product on a Caliper instrument, and calculating the obtained value as the inhibition rate according to the following formula: inhibition = (positive control value-test well value)/(positive control value-negative control value) × 100. Curves were fitted on XLFit version5.4.0.8 and compound concentration IC at 50% inhibition was calculated 50 See table 1.
TABLE 1 IC for enzymatic inhibition of human SIK1 by the compounds of this disclosure 50 Value of
| Example numbering | IC 50 (nM) | Imax(％) |
| 1 | 634 | 96 |
| 2 | 206 | 98 |
| 3 | 1245 | 91 |
| 4 | 561 | 94 |
| 6 | 466 | 97 |
| 7 | 628 | 96 |
| 8 | 469 | 96 |
And (4) conclusion: the compounds of the present disclosure have weak inhibitory effect on SIK 1.
Test example 2
Test example 2 inhibition of human SIK2 kinase by Compounds of the disclosure
Experimental materials and instruments
SIK2 enzyme (Promega, VA 7267)
2.ADP-Glo TM Kinase reagent (Promega, V9101)
3.DMSO(Sigma,D2650)
4. Magnesium chloride solution (Sigma, M1028-100 ML)
Tris pH7.5 2M (Biyuntian, B548139-0500)
6.Triton X-100(Sigma,T8787-100ML)
7.EGTA(Sigma,E3889-100G)
DTT 2M (Biotechnology, B645939)
9.96-well plate (Corning, 3795)
10.384-orifice plate (Corning, 4513)
11. Sterile pure water (homemade Hengrui Shanghai)
12.15mL centrifuge tube (Corning)
13. Constant temperature box (Shanghai-Heng scientific instruments Co., ltd.)
PHERAstar FS microplate reader (BMG Labtech)
Second, experimental procedure
SIK2 is a kinase that phosphorylates the substrate AMARA in the presence of ATP. The ADP-Glo detection kit is an ADP detection reagent based on a luminescence method, and can be used for detecting the change of the enzyme activity of SIK 2. The operation of the kit is carried out in three steps: 1) AMARA as a substrate, which is phosphorylated in the presence of ATP to produce ADP; 2) After the ADP generation reaction is completed, adding ADP-Glo reagent to terminate the reaction and consume the rest ATP; 3) Adding a kinase detection reagent to convert ADP into ATP and convert ATP into optical signals in coupled luciferase/luciferin reaction, thereby detecting the change of enzyme activity.
Diluting 20mM of the test compound dissolved in 100% DMSO to 1mM by 100% DMSO, which is a concentration 100 times the highest concentration point of the compound in the reaction system, diluting the compound at this concentration by 4 times by 10 concentration points in 100% DMSO, and making the blank well 100% DMSO. Diluting the serially diluted compounds and 100% (v/v) DMSO in water to 5X concentration by 20 times, and mixing well; mu.L of 5 Xconcentration compound was taken in the reaction wells, and 1. Mu.L of 5% DMSO was added to the negative control wells (no enzyme added) and the positive control wells (no compound added with enzyme). SIK2 enzyme and AMARA were diluted to 2.5-fold concentration in reaction buffer (25mM tris, ph7.5, 0.01% triton X-100,0.5mM egta,5mM magnesium chloride, 2.5mM DTT) (final reaction concentration SIK2:0.37nm AMARA. ATP was diluted to 2.5-fold concentration in the reaction buffer (final reaction concentration: 5. Mu.M), and 2. Mu.L was transferred to the reaction system. The 5. Mu.L reaction was mixed well and incubated at room temperature for 120 minutes. The reaction was stopped by adding 5. Mu.L of ADP-Glo reagent and incubated at room temperature for 40min to deplete the remaining ATP. Then 10. Mu.L of kinase detection reagent was added and incubated at room temperature for 30min. After that, the obtained value is read according toThe following formula is calculated as the inhibition ratio: inhibition =100-100 (testwell number-negative control value)/(positive control value-negative control value). The inhibition curve is drawn according to each concentration of the compound and the corresponding inhibition rate by Graphpad Prism software, and the concentration of the compound when the inhibition rate reaches 50 percent, namely IC is calculated 50 The values are shown in Table 2.
TABLE 2 IC for enzymatic inhibition of human SIK2 by the compounds of this disclosure 50 Value of
| Example numbering | IC 50 (nM) | Imax(％) |
| 1 | 7 | 100 |
| 2 | 14 | 100 |
| 3 | 17 | 100 |
| 4 | 8 | 97 |
| 5 | 11 | 101 |
| 6 | 10 | 101 |
| 7 | 10 | 102 |
| 8 | 10 | 101 |
And (4) conclusion: the disclosed compound has a good inhibition effect on SIK 2. By comparing test example 1 with test example 2, it can be seen that the compound of the present disclosure has a selective inhibitory effect on SIK 2.
Test example 3 inhibition of human SIK3 kinase by Compounds of the disclosure
1. Experimental materials and instruments
SIK3 enzyme (Promega, VA 7300)
2.ADP-Glo TM Kinase Assay(Promega,V9101)
3.DMSO(Sigma,D2650)
4. Magnesium chloride solution (Sigma, M1028-100ML,)
Tris PH7.5 2M (Biyuntian, B548139-0500)
6.Tritoon X-100(Sigma,T8787-100ML)
7.EGTA(Sigma,E3889-100G)
DTT 2M (Biotechnology, B645939)
9. 96-well plate(Corning,3795)
10. 384-well plate(Corning,4513)
11. Sterile pure water (homemade Hengrui Shanghai)
12.15mL centrifuge tube (Corning)
13. Constant temperature box (Shanghai-Heng scientific instruments Co., ltd.)
PHERAstar FS microplate reader (BMG Labtech)
2. Experimental procedure
SIK3 is a kinase that phosphorylates AMARA, a substrate, in the presence of ATP. The ADP-Glo detection kit is an ADP detection reagent based on a luminescence method, and can be used for detecting the change of the enzyme activity of SIK3. The operation of the kit is carried out in three steps: 1) AMARA as a substrate, which is phosphorylated in the presence of ATP to produce ADP; 2) After completion of the ADP production reaction, adding an ADP-Glo reagent to terminate the reaction and consume the remaining ATP; 3) Adding a kinase detection reagent, converting ADP into ATP, and converting ATP into a light signal in coupled luciferase/luciferin reaction, thereby detecting the change of enzyme activity.
The 20mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 1mM, which is the 100X concentration of the highest concentration point of the compound in the reaction system, and the compound at this concentration was diluted 4-fold with 100% DMSO to 10 concentration points, and the blank well was 100% DMSO. The serially diluted compounds and 100% DMSO were further diluted 20-fold in water to 5 Xconcentration and mixed well; mu.L of 5 Xconcentration compound was taken in the reaction wells, and 1. Mu.L of 5% DMSO was added to the negative control wells (no enzyme added) and the positive control wells (no compound added with enzyme). SIK3 enzyme and AMARA were diluted to 2.5 × concentration (final Reaction concentration SIK3:10nm AMARA. ATP was diluted in Reaction buffer to 2.5 Xconcentration (final Reaction concentration 5. Mu.M), and 2. Mu.L was transferred to the Reaction system. After 5. Mu.L of the reaction was mixed well, the mixture was incubated at room temperature for 120 minutes. The reaction was stopped by adding 5. Mu.L ADP-Glo reagent and incubated at room temperature for 40min to deplete the remaining ATP. Then 10. Mu.L of kinase detection reagent was added and incubated at room temperature for 30min. After reading, the resulting value was calculated as the inhibition according to the following formula: inhibition =100-100 × (test well value-negative control value)/(positive control value-negative control value). Using Graphpad Prism software to draw an inhibition curve according to each concentration of the compound and the corresponding inhibition rate, and calculating the concentration of the compound when the inhibition rate reaches 50%, namely IC 50 The value is obtained.
TABLE 3 IC of enzymatic inhibition of human SIK3 by the compounds of the present disclosure 50 Value of
| Example numbering | IC 50 (nM) | Imax(％) |
| 4 | 17 | 96 |
And (4) conclusion: the disclosed compound has a good inhibitory effect on SIK3, and the selective inhibitory effect of the disclosed compound on SIK3 can be obtained by comparing test example 1 with test example 3.
Test example 4 inhibitory Activity of the Compound of the present invention on TNF α secretion from human monocytes stimulated with LPS
1. Experimental materials and instruments
1. Magnetic bead for separating human CD14 monocyte (Meitian and whirlwind, 130-050-201)
2. Human TNF-alpha enzyme-linked immune reaction kit (Xinbo Sheng, EHC103a.96.10)
3.DMSO(Sigma,D2650)
4. Human peripheral mononuclear cells (Miaoshun biology, PB 250F)
5.RPMI-1640(GE Healthcare,SH30809.01)
6. Fetal bovine serum (Gibco, 10099-141)
7. Phosphate Buffered Saline (PBS) PH7.4 (Yuanpeiya, B320)
8. Bovine Serum Albumin (BSA) (MP Biomedicals, 9048-46-8)
9.EDTA(0.5M),pH 8.0(Life technology,AM9260G)
10. Lipopolysaccharide (LPS) (Sigma, L2880)
11.96 hole round bottom plate (Corning, 3788)
LS magnetic pole (beautiful and gentle, 130-042-401)
13. Carbon dioxide incubator (Thermo scientific, i 160)
14.15 ml centrifuge tube (Corning)
15. Biological safety cabinet (Shanghai Li Shen scientific instruments Co., ltd., HFsafe-1200 LC)
16. High speed refrigerated centrifuge (Thermo scientific, ST 40R)
17. Plate washing machine (Bio Tek Instruments,405 TSU)
18. Constant temperature box (Shanghai-Heng scientific instruments Co., ltd.)
PHERAstar FS microplate reader (BMG Labtech)
2. Experimental procedure
Human peripheral blood mononuclear cells secrete a variety of cytokines upon stimulation by pathogens such as lipopolysaccharides. Among these factors are pro-inflammatory cytokines (e.g., TNF. Alpha., IL-6, IL-. Beta., etc.) that promote inflammatory responses, and cytokines that inhibit inflammatory responses or act as immunomodulating agents. In the experiment, the content of TNF alpha in a culture medium for culturing human peripheral blood mononuclear cells is detected by an Elisa method, and the inhibition or promotion effect of the compound on the release of the cytokines is evaluated.
Human peripheral blood mononuclear cells were cultured in RPMI1640 medium (hereinafter referred to as complete medium) containing 10% fetal bovine serum. The CD14+ monocyte isolation buffer was a PBS solution containing 0.5% BSA and 2mM EDTA. The LPS powder was dissolved in sterile water to 1mg/mL and stored in a refrigerator at-20 ℃ in portions.
Monocyte isolation and LPS treatment: centrifuging PBMC at 300g at 4 ℃ for 10min, carefully sucking off supernatant, re-suspending cells with a proper volume of pre-cooled cell separation buffer solution, counting, adjusting the cell concentration to 10^7 per 80 mu L of separation buffer solution, fully and gently blowing the cells uniformly, adding CD14+ cell sorting magnetic beads according to the proportion of 20 mu L magnetic beads per 10^7 cells, fully and uniformly mixing, placing in a refrigerator at 4 ℃ for incubation for 15 min, and shaking uniformly for several times. Adding 2mL of buffer solution into each 10^7 cells, adding precooled buffer solution, reversing, uniformly mixing, then centrifuging at the temperature of 4 ℃ for 10min. And (3) placing the LS cell collection column on a magnetic frame while waiting for centrifugation, placing a waste liquid collection tube below the LS cell collection column, and adding 3mL of precooling buffer solution to rinse the LS column. Resuspend the cell pellet at a ratio of 0.5-1mL buffer per 10^8 cells, and add to the LS column. When the magnetic beads bound to the cells flow through the LS column, they are attracted by the magnetic force, and the cells not bound to the magnetic beads flow away from the column. The LS column was rinsed three times with 3mL of pre-chilled buffer. And (3) replacing the cell collecting pipe, placing the cell collecting pipe under the LS column, adding 5mL culture medium into the LS column, taking the LS column off the magnetic frame, installing a piston to stably and uniformly push the cells out of the LS column, and collecting the cells into the cell collecting pipe. The collected cells were counted and diluted to 6.25X 10^6/mL with complete medium, 160. Mu.L of cell suspension was added per well in a 96-well round bottom plate to make the total number of seeded cells 1X 10^5 per well, and the cells were transferred to an incubator for 4 hours.
The 20mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 5mM, which is a 500X concentration of the highest concentration point of the compound in the reaction system, and the compound at this concentration was diluted 4-fold with 100% DMSO to 9 concentration points, and the blank well was 100% DMSO. The serially diluted compounds and 100% dmso were further diluted 50-fold in complete medium to 10 × concentration and mixed well; 20 μ L of 5 Xconcentration compound was taken in cell culture wells, and 20 μ L of 2% DMSO was added to negative control wells (no LPS added) and positive control wells (no LPS added compound). LPS stock (1 mg/mL) was diluted 500-fold to 2. Mu.g/mL with complete medium, 20. Mu.L of LPS solution was added to each well to give a final concentration of 200ng/mL of LPS, and shaken well by hand. Placing the cells back at 37 ℃,5% CO 2 Incubators were used to incubate and 20 hours later, the supernatants were collected for Elisa experiments.
ELISA to detect TNF α secretion levels: detection of cytokines in cell culture media was performed according to the Elisa kit instructions. Using standards&The specimen universal diluent dissolves the standard and is diluted to the following concentrations as a standard curve: 1000. 500, 250, 125, 62.5, 15.6, 0pg/mL. Using the sample as a standard&Diluting the specimen by proper times with universal diluent, and adding standard substance into blank holes&The general diluent of the specimen, the specimen or standard substances (100 mu L/hole) with different concentrations are added into the other corresponding holes, the reaction holes are sealed by sealing plate gummed paper, and the reaction holes are incubated for 90 minutes in a constant temperature box at 37 ℃ in a dark place. 20 minutes before use, diluted with biotinylated antibody30 × concentrated biotinylated antibody was diluted to 1 × working solution. The plate was washed 5 times with a plate washer at 300. Mu.L/well. Biotinylated antibody working solution (100. Mu.L/well) was added to each well. The reaction wells were sealed with new sealing plate gummed paper and incubated at 37 ℃ in a thermostated container for 60 minutes in the absence of light. The 30 Xconcentrated enzyme conjugate was diluted to 1 Xworking solution with the enzyme conjugate diluent 20 minutes prior to use. The plate was washed 5 times with a plate washer at 300. Mu.L/well. Add enzyme conjugate working solution (100. Mu.L/well) to each well. The reaction wells were sealed with new sealing plate gummed paper, incubated at 37 ℃ in a thermostated container for 30 minutes in the absence of light. The plate was washed 5 times with a plate washer at 300. Mu.L/well, the plate was dried, 100. Mu.L/well of a chromogenic substrate (TMB) was added, and incubated at 37 ℃ in a thermostat for 15 minutes in the absence of light. Add 100. Mu.L/well of the reaction stop solution, mix well and measure OD450 value within 3 minutes. The TNF α concentration per well obtained from the standard curve was calculated as the inhibition according to the following formula: inhibition =100-100 × (test well value-negative control value)/(positive control value-negative control value). Using Graphpad Prism software to draw an inhibition curve according to each concentration of the compound and the corresponding inhibition rate, and calculating the concentration of the compound when the inhibition rate reaches 50%, namely IC 50 The value is obtained.
TABLE 4 inhibition of TNF α secretion by LPS-stimulated human monocytes by the compounds of the disclosure IC 50 Value of
And (4) conclusion: the disclosed compound has good inhibition effect on TNF alpha secretion of human monocytes stimulated by LPS.
Test example 5 pharmacokinetic evaluation
1. SD rat test
1. Abstract
The drug concentration in plasma of SD rats at various times after gavage (i.g.)/intravenous injection (i.v.) administration of the compound of the present disclosure was measured by LC/MS method using SD rats as test animals. The pharmacokinetic behavior of the compounds of the present disclosure was studied in SD rats and evaluated for their pharmacokinetic profile.
2. Test protocol
2.1 test drugs
A compound 1.
2.2 test animals
The SD rats are divided into 2 groups of 8 male and female half, and provided by Zhejiang Untonlihua laboratory animal technology Co. After fasting overnight, the administration was by gavage and intravenous injection, respectively.
2.3 pharmaceutical formulation
A certain amount of test compound is weighed respectively, and then added with 5% DMSO +5% Tween 80+90% normal saline to prepare 0.2mg/mL colorless clear solution (intragastric administration group) and 0.2mg/mL colorless clear solution (intravenous administration group).
2.4 administration of drugs
The intragastric administration group: the dose was 2.0mg/kg and the volume was 10.0mL/kg.
Intravenous administration group: the dose was 1.0mg/kg and the volume was 5.0mL/kg.
3. Operation of
And (3) intragastric administration group: 0.2mL of blood is collected from the orbit at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours before and after administration, the blood is placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000rpm for 2 minutes (4 ℃), plasma is separated within 1 hour, and the blood is stored with dry ice for testing. The blood collection to centrifugation process is operated under ice bath condition. Food was consumed 2 hours after dosing.
Group for intravenous administration: blood was collected before administration and 5 minutes, 30 minutes, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, and the group administered with intragastric administration was treated.
Determination of the content of the test compounds in the plasma of SD rats after administration of the drugs at different concentrations: SD rat plasma samples were taken at 50. Mu.L each at time post-dose, 25. Mu.L of tolbutamide (2 ug/mL) was added to each sample, and the protein was precipitated with 450. Mu.L of acetonitrile, vortexed, and centrifuged at 3700rpm for 10 minutes. 0.5. Mu.L of the supernatant was analyzed by LC/MS/MS.
4. Pharmacokinetic parameter results
TABLE 5 pharmacokinetic parameters of the compounds of this disclosure in SD rats
And (4) conclusion: the compound disclosed by the invention has good drug absorption activity in an SD rat body and pharmacokinetic advantage.
Claims (20)
1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is N, X 2 Is C; or, X 1 Is C, X 2 Is N;
R 1 is-L- (CR) 7 R 8 ) s -A-B；
L is selected from the group consisting of a bond, O and S;
a is heterocyclyl, wherein said heterocyclyl is optionally selected from halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -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) 2 R J1 、-S(O) 2 NR g1 R h1 Aryl and heteroaryl, or a pharmaceutically acceptable salt thereof;
b is selected from-C (O) R 9 ；
R 9 Selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, -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) 2 R J2 、-S(O) 2 NR g2 R h2 Aryl and heteroaryl, substituted with one or more substituents;
R 7 and R 8 The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, cyano, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, and cycloalkyl;
G 1 is CR 3 Or an N atom;
R 2 、R 3 、R 4 and R 6 The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkenyl groups, alkynyl groups, cyano groups, nitro groups, hydroxy groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, amino groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein said alkenyl groups, alkynyl groups, alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, cyano groups, nitro groups, hydroxy groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, amino groups, oxo groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R 5 selected from the group consisting of hydrogen, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, and-NR 5a R 5b Wherein said alkenyl, alkynyl, alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 5a and R 5b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;
R w is-NR w1 R w2 or-NR w3 -；
R w1 Selected from the group consisting of alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R w2 and R w3 Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkenyl groups, alkynyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
when R is w is-NR w3 When the N atom is not in contact with R 5 Together forming a heterocyclyl group, said heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R f1 and R f2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R g1 、R h1 、R g2 and R h2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkyneAlkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or R g1 And R h1 To the bound N atom, R g2 And R h2 Together with the attached N atom, form a heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R J1 and R J2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
p is 1,2 or 3;
s is 0, 1,2,3 or 4.
2. The compound according to claim 1, which is a compound represented by the general formula (III):
wherein:
ring a is a 3-to 12-membered heterocyclic group containing at least one nitrogen atom;
R 10 the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, oxo, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, amino, aryl, and heteroaryl;
R y the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
t is 1,2 or 3;
n is 0, 1 or 2;
m is 0, 1,2,3 or 4;
L、X 1 、X 2 、G 1 、R 2 、R 4 、R 6 、R 9 、R w3 p and s are as defined in claim 1.
3. A compound according to claim 1 or2, or a pharmaceutically acceptable salt thereof, wherein R 2 Is a hydrogen atom.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein G 1 Is CR 3 ；R 3 Is C 1-6 An alkoxy group.
5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 4 And R 6 Are all hydrogen atoms.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 9 Is a 3-to 8-membered cycloalkyl group or a 3-to 12-membered heterocyclyl group, wherein said 3-to 8-membered cycloalkyl group and said 3-to 12-membered heterocyclyl group are each independently optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy and oxo.
7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 10 Is a hydrogen atom.
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R w3 Is C 1-6 A haloalkyl group.
9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein n is 1; and/or, R y Is a hydrogen atom.
10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1 or 2.
11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein L is a bond or O.
12. A compound according to any one of claims 2 to 11, or a pharmaceutically acceptable salt thereof, wherein
Is composed of
W is C, CH or N;
is a single bond or a double bond; r is 10 And t is as defined in claim 2; preferably, the first and second electrodes are formed of a metal,
is composed of
13. A compound, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
14. a compound represented by the general formula (IIIA):
wherein:
R 10 is a hydrogen atom;
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 claim 2.
15. A compound or salt thereof according to claim 14, selected from the following compounds:
16. a process for the preparation of a compound of formula (III) according to claim 2 or a pharmaceutically acceptable salt thereof, which comprises:
nucleophilic substitution reaction is carried out between the compound shown in the general formula (IIIA) or the salt thereof and the compound shown in the general formula (IIB) or the salt thereof to obtain the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Cl;
ring 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 2.
17. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
18. Use of a compound of general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the manufacture of a medicament for inhibiting SIK2 and/or SIK3.
19. Use of a compound of general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 for the preparation of a medicament for the treatment and/or prevention of a disease or disorder selected from inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving cartilage turnover injury, congenital cartilage malformations, diseases involving bone turnover injury, diseases associated with excessive secretion of TNF α, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases and diseases associated with abnormal angiogenesis; preferably, wherein said disease or disorder is an inflammatory disease or an autoimmune disease.
20. The use according to claim 19, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic Obstructive Pulmonary Disease (COPD), asthma, bronchitis, inflammatory bowel disease, systemic Lupus Erythematosus (SLE), cutaneous Lupus Erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune liver disease, sjogren's syndrome, multiple sclerosis, dry eye disease, type I diabetes and complications associated therewith, atopic eczema, thyroiditis, contact dermatitis, sjogren's syndrome, and amyotrophic lateral sclerosis; wherein said inflammatory bowel disease is preferably ulcerative colitis or Crohn's disease.
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| CN116813608B (en) * | 2023-06-08 | 2024-03-22 | 英矽智能科技(上海)有限公司 | Thiazole compound and application thereof |
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