Oxaazabicyclic derivatives, preparation methods thereof and their applications in medicine

Abstract

The present disclosure relates to oxazabicyclic derivatives, their preparation methods, and their pharmaceutical applications. Specifically, the present disclosure relates to an oxazabicyclic derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, particularly as a PI3Kδ inhibitor and in the preparation of a medicament for treating conditions or disorders ameliorated by PI3Kδ inhibition. #imgabs0#

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to an oxazabicyclic derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, in particular, its use as a PI3Kδ inhibitor and its use in the preparation of a medicament for treating conditions or disorders improved by inhibiting PI3Kδ. Background Art

[0002] Phosphoinositide 3-kinase (PI3K) is a key regulatory kinase in the PI3K / AKT / mTOR signaling pathway, involved in regulating cell proliferation, differentiation, apoptosis, and angiogenesis. Abnormal activation of PI3K is closely related to the occurrence and development of various tumors, and different types of PI3K play different functions. There are four PI3K isoforms: α, β, γ, and δ. PI3Kδ is mainly present in immune cells and blood cells, and is closely related to the occurrence of immune and blood tumors and inflammation (Cell, 170(4), 605-635).

[0003] PI3Kδ is primarily expressed in immune and hematopoietic cells, participating in BCR signaling in B cells and controlling the development and maturation of B cells in the body. When antigens are present, specific surface immunoglobulins (Ig) on the BCR surface bind to the antigen, leading to phosphorylation of the ITAMs within the intracellular domain of the CD79A / B complex. Phosphorylated ITAMs recruit and activate SYK, which in turn activates BTK and its downstream molecule, PLCγ2. Activated SYK binds to the p85 subunit of PI3Kδ, activating PI3Kδ and promoting the production of PIP3. The generated PIP3 recognizes and interacts with the N-terminal domain of BTK, mediating its recruitment to the membrane and thereby activating BTK-mediated B cell signaling and inducing the expression of numerous related genes. Furthermore, phosphorylated CD19 can recruit PI3Kδ to the cell membrane, activating PI3Kδ, catalyzing the production of PIP3 from PIP2, and activating AKT, promoting cell proliferation, migration, and apoptosis (N Engl J Med, 379, 2052-2062). In addition to regulating B cell function, recent studies have reported that PI3Kδ activation can promote the development, maturation, and recruitment of Treg cells (Cancer Immunol Res, 2, 1080-1089). Inhibition of PI3Kδ can promote the proliferation and survival of CD8+ memory T cells (Cancer Res, 77, 4135-4145). Therefore, PI3Kδ is an ideal target for the treatment of B cell lymphomas, and the development of selective PI3Kδ inhibitors as therapeutics for hematologic malignancies is gaining increasing attention.

[0004] Idelalisib was the first PI3Kδ selective inhibitor approved for marketing, and was approved in 2014 for the treatment of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and small lymphocytic lymphoma (SLL). Subsequently, in 2018, duvelisib (which acts on both PI3Kδ and γ) was approved for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). Although PI3Kδ inhibitors have achieved very good results in the treatment of these hematological malignancies, these early inhibitors generally had poor selectivity for PI3K kinases, resulting in a number of drug-related hepatotoxic and gastrointestinal side effects seen in the clinic. To further reduce the potential side effects of PI3Kδ inhibitors, many companies have been actively developing second-generation, highly selective PI3Kδ inhibitors in recent years. Representative ones include parsaclisib, ME-401, and IOA-244, which are currently in different clinical stages.

[0005] IOA-24 is a second-generation PI3Kδ inhibitor developed by iOnctura (WO2011058149, WO2014121901). Compared with traditional PI3Kδ inhibitors, it is an ATP non-competitive inhibitor. This feature makes this drug highly selective for inhibiting PI3Kδ isoforms.

[0006] Considering that the side effects of the first-generation PI3Kδ inhibitors currently on the market are relatively obvious, which limits the use of this type of drug in more patient populations, there is a significant unmet medical need for the development of second-generation highly selective PI3Kδ inhibitors in relevant patient populations.

[0007] Currently published related patent applications include WO2011058149A1, WO2015196759A1, WO2015196335A1, WO2014209980A1, WO2004069824A1, etc. Summary of the Invention

[0008] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] R 5is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH2) s NR 7 R 8 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 、-NR 6 SO2R 9 and R are substituted by one or more substituents, wherein R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and each of the R is independently optionally selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH2) s NR 7 R 8 、-OR 9 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl;

[0012] R 1 the same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxy, hydroxyalkyl, -(CH2) s NR 7 R 8 , cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, cyano, nitro, -(CH2) s NR 7 R 8 AND-OR 9 When m is greater than or equal to 2, the two R 1 It can form a spiro or bridged ring system on the heterocycle to which it is connected;

[0013] R 2 and R 4are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl and heteroarylalkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halogen, cyano, nitro, -(CH2) s NR 7 R 8 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 and -NR 6 SO2R 9 is substituted by one or more substituents in;

[0014] R 3 the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH2) s NR 7 R 8 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 、-NR 6 SO2R 9 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halogen, cyano, nitro, -(CH2) s NR 7 R 8 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 and -NR 6 SO2R 9 is substituted by one or more substituents in;

[0015] or two adjacent R 3 Together with the carbon atom to which it is attached, it forms a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is each independently optionally substituted with one or more substituents selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0016] R 6 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, and an aryl group, wherein the alkyl group, the cycloalkyl group, and the aryl group are each independently optionally substituted by one or more substituents selected from an alkyl group, an alkoxy group, an oxo group, a halogen group, an amino group, a cyano group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0017] R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0018] or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0019] R 9 Each is independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH2) s NR 7 R 8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;

[0020] m is 0, 1, 2, 3, 4 or 5;

[0021] n is 1 or 2;

[0022] q is 0, 1, 2, 3, or 4;

[0023] s is 0, 1, 2, 3, 4, or 5; and

[0024] t is 0, 1, or 2.

[0025] In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (I-1) or (I-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0026]

[0027] where R 1 -R 5 , n, q and m are as defined in the general formula (I).

[0028] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 5 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is independently selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH2) s NR 7 R 8 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 、-NR 6 SO2R 9 and R are substituted by one or more substituents, wherein R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and each of the R is independently optionally selected from halogen, alkyl, haloalkyl and -OR 9 is substituted by one or more substituents in;

[0029] R 6 -R 9 , s and t are as defined in the general formulae (I), (I-1) and (I-2).

[0030] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 5is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is each independently optionally substituted by one or more R, wherein R is selected from cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and the R is each independently optionally substituted by one or more substituents selected from halogen, alkyl and haloalkyl;

[0031] Preferably, R 5 is an aryl group, wherein the aryl group is optionally substituted by a heterocyclylalkyl group, and the heterocyclylalkyl group is optionally substituted by one or more substituents selected from halogen, alkyl and haloalkyl;

[0032] More preferably, R 5 is phenyl, said phenyl being substituted by morpholinylmethyl, and even more preferably, R 5 for

[0033] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 5 is a 6-10 membered aryl group, wherein the 6-10 membered aryl group is optionally replaced by a 3-6 membered heterocyclic group C 1-6 Alkyl substituted, the 3-6 membered heterocyclic group C 1-6 Alkyl is optionally selected from halogen, C 1-6 Alkyl and C 1-6 The haloalkyl group is substituted by one or more substituents.

[0034] In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0035]

[0036] in

[0037] R 10 the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH2) s NR 7 R 8 、-OR 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and -(CH2)s NR 7 R 8 is substituted by one or more substituents in;

[0038] R 11 the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, nitro, -(CH2) s NR 7 R 8 , cycloalkyl, cycloalkyloxy, and cycloalkylalkyl;

[0039] R 12 the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH2) s NR 7 R 8 、-OR 9 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; when u is greater than or equal to 2, the two R 12 Spirocyclic or bridged ring systems can be formed on the morpholine ring;

[0040] w is 0, 1, 2, 3, or 4;

[0041] u is 0, 1, 2, 3, 4, 5, or 6;

[0042] R 1 -R 4 、R 7 -R 9 , s, m and q are as defined in the general formula (I).

[0043] In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II-1) or (II-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0044]

[0045] where R 1 -R 4 、R 10 -R 12 , q, u, w and m are as defined in the general formula (II).

[0046] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 1 the same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxyalkyl, -(CH2) s NR 7 R 8 , cycloalkyl, cycloalkylalkyl, cycloalkyloxy, wherein the alkyl and cycloalkyl are each independently optionally selected from halogen, alkyl, haloalkyl, cyano and -OR 9 When m is greater than or equal to 2, the two R 1 A spiro or bridged ring system can be formed on the oxygen-containing heterocycle; wherein R 7 -R 9 and s are as defined in the general formulae (I), (I-1), (I-2), (II), (II-1) and (II-2).

[0047] Preferably, R 1 The same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy and haloalkoxy, wherein the alkyl is optionally selected from halogen, cyano and -OR 9 is substituted by one or more substituents; wherein R 9 As defined in general formula (I), (I-1), (I-2), (II), (II-1) and (II-2).

[0048] More preferably, R 1 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; more preferably hydrogen.

[0049] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 2 and R 4 The same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl and cycloalkylalkyl, wherein the alkyl and cycloalkyl are each independently optionally selected from alkyl, haloalkyl, halogen, cyano and -OR 9 is substituted by one or more substituents; wherein R 9 As defined in general formula (I), (I-1), (I-2), (II), (II-1) and (II-2).

[0050] Preferably, R 2 and R 4 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; More preferably, R 2 and R 4 All are hydrogen.

[0051] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 3 the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH2) s NR 7 R 8 AND-OR 9 ; where R 7 -R 9 and s are as defined in the general formulae (I), (I-1), (I-2), (II), (II-1) and (II-2).

[0052] Preferably, R 3 The same or different, each independently selected from hydrogen, halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl;

[0053] More preferably, R 3 the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl;

[0054] More preferably, R 3 the same or different, each independently selected from fluoro, chloro, methyl, methoxy and trifluoromethyl;

[0055] More preferably, R 3 For fluorine.

[0056] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 6 is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, hydroxy and hydroxyalkyl;

[0057] Preferably, R 6 A hydrogen atom or C 1-6 alkyl.

[0058] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a cycloalkyl group; or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, hydroxyalkyl and cycloalkyl;

[0059] Preferably, R 7 and R 8 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally selected from C 1-6 Alkyl, C 1-6 The alkyl group is substituted by one or more substituents selected from alkoxy and halogen.

[0060] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 9 independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano and amino;

[0061] Preferably, R 9 Independently selected from hydrogen atom, alkyl, haloalkyl and cycloalkyl; wherein the alkyl and cycloalkyl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy and haloalkyl.

[0062] More preferably, R 9 are independently selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl and 3-6 membered cycloalkyl; wherein the C1-6 Alkyl and 3-6 membered cycloalkyl are each independently optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The haloalkyl group is substituted by one or more substituents.

[0063] In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 10 the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH2) s NR 7 R 8 AND-OR 9 ; where R 7 -R 9 and s are as defined in the general formula (I).

[0064] Preferably, R 10 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; more preferably hydrogen.

[0065] In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano and -(CH2) s NR 7 R 8 ; where R 7 -R 8 and s are as defined in general formulae (II), (II-1) and (II-2).

[0066] Preferably, R 11 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; more preferably hydrogen.

[0067] In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 12 the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH2)s NR 7 R 8 AND-OR 9 ; where R 7 -R 9 and s are as defined in general formulae (II), (II-1) and (II-2).

[0068] Preferably, R 12 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; more preferably hydrogen or methyl; further preferably hydrogen.

[0069] In some preferred embodiments of the present disclosure, a compound represented by the general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein m is 0, 1 or 2, preferably 0.

[0070] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0071] In some preferred embodiments of the present disclosure, a compound represented by the general formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, 2 or 3, preferably 1 or 2, and more preferably 1.

[0072] In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein u is 0, 1, 2 or 3, preferably 0.

[0073] In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein w is 0, 1 or 2, preferably 0.

[0074] In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) or (II-2) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 1the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; m is 0, 1 or 2; R 2 and R 4 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; R 3 The same or different, each independently selected from hydrogen, halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkyl; q is 0, 1, 2 or 3; R 10 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; w is 0, 1 or 2; R 11 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; R 12 the same or different, each independently selected from hydrogen, halogen and C 1-6 Alkyl; u is 0, 1, 2 or 3.

[0075] Table A Typical compounds of the present disclosure include, but are not limited to:

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0085] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, the method comprising the following steps:

[0086]

[0087] The compound of the general formula (IA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its salt is reacted with the compound of the general formula (IB) or its salt to obtain the compound of the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0088] where R 1 -R 5 , n, q and m are as defined in the general formula (I).

[0089] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, the method comprising the following steps:

[0090]

[0091] The compound of general formula (IIA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its salt is reacted with the compound of general formula (IIB) or its salt to obtain the compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0092] where R 1 -R 4 、R 10 -R 12 , q, u, w and m are as defined in the general formula (II).

[0093] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0094] The present disclosure further relates to the use of compounds represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for inhibiting PI3Kδ.

[0095] The present disclosure further relates to the use of compounds represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing PI3Kδ-mediated diseases.

[0096] The present disclosure further relates to the use of the compounds of formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of medicaments for treating and / or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases; in particular, the cancer and related diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urinary tract cancer, urethral cancer, cervical cancer, ovarian cancer, breast cancer, urinary tract cancer, urethral ... The present invention relates to a leukemia, a leukemia, a leukemia of the head and neck, a ureteral tumor, a prostate cancer, a seminoma, a testicular tumor, a leukemia, a head and neck tumor, an endometrial cancer, a thyroid cancer, a lymphoma, a sarcoma, an osteoma, a neuroblastoma, a neuroblastoma, a neuroendocrine cancer, a brain tumor, a CNS cancer, a myeloma, an astrocytoma, a glioblastoma and a glioma; the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia; the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal Marginal zone lymphoma, T cell lymphoma, B cell lymphoma and diffuse large B cell lymphoma; the lung cancer is preferably non-small cell lung cancer or small cell lung cancer; the myeloma is preferably multiple myeloma (MM); the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behcet's disease, celiac disease, anti-glutaminase, Chagas' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome, Graves' disease, Fuzzy's disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha-globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff-man syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia and Wegener's granulomatosis; the lupus is preferably lupus erythematosus or systemic lupus erythematosus;The pemphigus is preferably pemphigus vulgaris, the liver cancer is preferably hepatocellular carcinoma, the head and neck tumor is preferably head and neck squamous cell carcinoma, the sarcoma is preferably osteosarcoma or soft tissue sarcoma, and the colorectal cancer is preferably colon cancer or rectal cancer.

[0097] The present disclosure also relates to a method for inhibiting PI3Kδ, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or as shown therein, or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0098] The present disclosure also relates to a method for treating and / or preventing PI3Kδ-mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0099] The present disclosure also relates to a method for treating and / or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and shown in Table A or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in particular, the cancer and related diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, Bladder cancer, urothelial carcinoma, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma; the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia; the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma , extranodal marginal zone lymphoma, T cell lymphoma, B cell lymphoma and diffuse large B cell lymphoma; the lung cancer is preferably non-small cell lung cancer or small cell lung cancer; the myeloma is preferably multiple myeloma (MM); the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behcet's disease, celiac disease, anti-glutaminase, Chagas' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha-globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff-man syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia, and Wegener's granulomatosis; the lupus is preferably systemic lupus erythematosus or systemic lupus erythematosus;The pemphigus is preferably pemphigus vulgaris, the liver cancer is preferably hepatocellular carcinoma, the head and neck tumor is preferably head and neck squamous cell carcinoma, the sarcoma is preferably osteosarcoma or soft tissue sarcoma, and the colorectal cancer is preferably colon cancer or rectal cancer.

[0100] The present disclosure further relates to a compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0101] The present disclosure also relates to compounds represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as PI3Kδ inhibitors.

[0102] The present disclosure also relates to compounds represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for treating and / or preventing PI3Kδ-mediated diseases.

[0103] The present disclosure also relates to compounds represented by general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A, or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and / or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases; the diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate ... cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma; the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia; the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T cell Lymphoma, B cell lymphoma and diffuse large B cell lymphoma; the lung cancer is preferably non-small cell lung cancer or small cell lung cancer; the myeloma is preferably multiple myeloma (MM); the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behcet's disease, celiac disease, anti-glutaminase, Chagas' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome, Graves' disease, Graves' disease, Ringling-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha-globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff-man syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia, and Wegener's granulomatosis; the lupus is preferably systemic lupus erythematosus or systemic lupus erythematosus;The pemphigus is preferably pemphigus vulgaris, the liver cancer is preferably hepatocellular carcinoma, the head and neck tumor is preferably head and neck squamous cell carcinoma, the sarcoma is preferably osteosarcoma or soft tissue sarcoma, and the colorectal cancer is preferably colon cancer or rectal cancer.

[0104] In the present disclosure, the PI3Kδ-mediated disease is selected from inflammatory diseases, autoimmune diseases, cancer and related diseases; preferably, the cancer and related diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma The leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia; the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T cell lymphoma, B cell lymphoma and diffuse large B cell lymphoma; the lung cancer is preferably non-small cell lung cancer or small cell lung cancer; the myeloma is preferably multiple myeloma (MM); the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, Arthritis, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behçet's disease, celiac disease, anti-glutaminase, Chagas' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha-globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus, lupus nephritis The present invention relates to a method for treating a lupus erythematosus (LSA) or systemic lupus erythematosus (SLE) or a combination of the following: lupus erythematosus (LSA) or systemic lupus erythematosus (SLE); lupus erythematosus (LSA) or systemic lupus erythematosus (SLE); pemphigus vulgaris (PPV); hepatocellular carcinoma (HCC); head and neck tumor (HNSC); sarcoma (OS) or soft tissue sarcoma (SSS); and colorectal cancer (CRC) or rectal cancer.

[0105] The active compound can be prepared into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous), inhalation or insufflation. The compounds of the present disclosure can also be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0106] As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form, or in a form that allows a patient to self-administer a single dose. A unit dosage form of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms may range from 0.1 to 1000 mg.

[0107] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0108] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0109] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0110] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0111] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0112] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0113] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0114] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0115] The disclosed compounds can 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 that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0116] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0117] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status 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, etc.; in addition, the optimal treatment method, such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0118] Terminology

[0119] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0120] 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 group containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12), and more preferably an alkyl group containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0121] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0122] 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 may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0123] 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 may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0124] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8), and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0125] The term " spiroalkyl " refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between the monocycle, which can contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between the rings, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0126]

[0127] Term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares the full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, and wherein one or more rings can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan).Can be divided into dicyclo, tricycle, tetracycle or polycyclic fused cycloalkyl according to the number of composition ring, be preferably dicyclo or tricycle, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan of dicycloalkyl.The limiting examples of fused cycloalkyl comprises:

[0128]

[0129] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0130]

[0131] The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferably

[0132] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0133] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0134] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1-4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms, of which 1-3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclyls.

[0135] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, one atom (called spiral atom) shared between the monocycles, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It can contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably a 3 / 5 member, 3 / 6 member, 4 / 4 member, 4 / 5 member, 4 / 6 member, 5 / 5 member or a 5 / 6 member monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0136]

[0137] The term "fused heterocyclic radical" refers to 5 to 20 yuan, and each ring in the system shares a polycyclic heterocyclic group of a pair of atoms adjacent to other rings in the system, and one or more rings can contain one or more double bonds, wherein one or more annular atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulphur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining annular atoms are carbon. Preferably, it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radicals, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radicals. The limiting examples of fused heterocyclic radicals include:

[0138]

[0139] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0140]

[0141] The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0142] wait.

[0143] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0144] 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 having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above 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:

[0145]

[0146] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0147] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, or 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, 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 connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0148]

[0149] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0150] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0151] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0152] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0153] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0154] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0155] The term "cycloalkylalkyl" refers to a cycloalkyl-alkyl- group in which cycloalkyl and alkyl are as defined above.

[0156] The term "heterocyclylalkyl" refers to a heterocyclyl-alkyl- group in which heterocyclyl and alkyl are as defined above.

[0157] The term "arylalkyl" refers to an aryl-alkyl- group in which aryl and alkyl are as defined above.

[0158] The term "heteroarylalkyl" refers to a heteroaryl-alkyl- group in which heteroaryl and alkyl are as defined above.

[0159] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0160] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0161] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0162] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0163] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0164] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0165] The term "hydroxy" refers to -OH.

[0166] The term "mercapto" refers to -SH.

[0167] The term "amino" refers to -NH2.

[0168] The term "cyano" refers to -CN.

[0169] The term "nitro" refers to -NO2.

[0170] The terms "oxo" and "oxo" refer to "=0".

[0171] The term "carbonyl" refers to C=O.

[0172] The term "carboxy" refers to -C(O)OH.

[0173] 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.

[0174] The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having the structure of the present disclosure, except that hydrogen is replaced by "deuterium" or "tritium", or by 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14Compounds in which a carbon atom is replaced by a deuterium atom (C-isotope) are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetics, or receptor studies. The present disclosure also includes various deuterated compounds. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art will be able to synthesize deuterated compounds with reference to relevant literature. When preparing deuterated compounds, commercially available deuterated starting materials can be used, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.

[0175] "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 and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0176] "Substituted" means that one or more hydrogen atoms, preferably 1-5, more preferably 1-3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

[0177] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0178] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and possess the desired biological activity. Salts can be prepared during the final isolation and purification of the compounds, or separately by reacting a suitable group with a suitable 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 and organic acids.

[0179] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active agent. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0180] As used herein, the term "solvate" refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0181] "Prodrug" refers to a compound that can be transformed in vivo under physiological conditions, for example, by hydrolysis in the blood, to yield the active prodrug.

[0182] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0183] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0184] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0185] Synthesis method of the disclosed compound

[0186] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0187] Option 1

[0188] The method for preparing the compound represented by the general formula (I) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprises the following steps:

[0189]

[0190] The compound of the general formula (IA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its salt, is reacted with the compound of the general formula (IB) or its salt under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound of the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0191] where R 1 -R 5 , n, q and m are as defined in the general formula (I).

[0192] Option 2

[0193] The method for preparing the compound represented by the general formula (II) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprises the following steps:

[0194]

[0195] The compound of general formula (IIA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its salt, is reacted with the compound of general formula (IIB) or its salt under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0196] where R 1 -R 4 、R 10 -R 12 , q, u, w and m are as defined in the general formula (II).

[0197] Option 3

[0198] The present invention discloses a method for preparing the compounds represented by general formula (I-1) and (I-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0199]

[0200] The general formula (I) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof are subjected to chiral resolution to obtain compounds of the general formula (I-1) and the general formula (I-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof;

[0201] Among them, R 1 -R 5, n, q and m are as defined in the general formula (I).

[0202] Option 4

[0203] The present invention discloses a method for preparing the compounds represented by general formula (II-1) and (II-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0204]

[0205] The general formula (II) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof are subjected to chiral resolution to obtain compounds of the general formula (II-1) and the general formula (II-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof;

[0206] where R 1 -R 4 、R 10 -R 12 , q, u, w and m are as defined in the general formula (II).

[0207] The reagents providing alkaline conditions in the above reaction include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

[0208] The condensing agent described in the above reaction includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7-azabenzotriazole)- benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate; preferably 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0209] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, toluene, xylene, pyridine, dioxane, N,N-dimethylacetamide or N,N-dimethylformamide and mixtures thereof. DETAILED DESCRIPTION

[0210] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0211] Example

[0212] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0213] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), or a THERMOULTIMATE 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0214] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0215] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0216] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0217] Chiral separation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0218] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0219] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0220] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0221] Average kinase inhibition rate and IC 50 The values were determined using a NovoStar microplate reader (BMG, Germany).

[0222] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0223] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0224] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0225] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0226] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0227] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0228] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0229] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0230] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C.

[0231] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0232] Example 1

[0233] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-fluoro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 1

[0234] ((1S,6R)-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-fluoro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 1-1

[0235] ((1R,6S)-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-fluoro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 1-2

[0236]

[0237] 6-Fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 1a (300 mg, 0.66 mmol, prepared by the method disclosed in the specification of "CN102695710B" on page 204 of the intermediate S81) and 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride 1b (98 mg, 0.72 mmol, Nanjing Yaoshi) were added to N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (255 mg, 1.97 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (324 mg, 0.85 mmol, HATU) were added sequentially with stirring, and the mixture was stirred at room temperature overnight. 50 mL of water was added, and the mixture was extracted three times with a mixed solvent of dichloromethane and methanol (v:v = 8:1). The organic phases were combined, washed sequentially with water and a saturated sodium chloride solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System A to give the title compound 1 (120 mg) in a yield of 33.9%.

[0238] MS m / z(ESI):539.1[M+1].

[0239] 1 H NMR (500MHz, DMSO-d6): δ7.61(brs,1H),7.54(brs,2H),7.46-7.52(m,3H),6.65-6.70(m,1H),5.03- 5.13(m,2H),3.54-3.89(m,6H),3.61(brs,4H),3.27-3.39(m,2H),2.40(brs,4H),0.77-0.85(m,2H).

[0240] Compound 1 (120 mg, 0.22 mmol) was subjected to chiral separation (separation conditions: CHIRALPAK IG chiral preparative column, 150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol = 80 / 20 (V / V), flow rate: 1 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title products 1-2 (25 mg) and 1-1 (30 mg).

[0241] Single configuration compound 1-2 (shorter retention time):

[0242] MS m / z(ESI):538.9[M+1].

[0243] Chiral HPLC analysis: retention time 25.63 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0244] 1 H NMR(500MHz,DMSO)δ7.61(brs,1H),7.54(brs,2H),7.46-7.52(m,3H),6.65-6.70(m,1H),5.03-5. 13(m,2H),3.54-3.89(m,6H),3.61(brs,4H),3.27-3.39(m,2H),2.40(brs,4H),0.77-0.85(m,2H).

[0245] Single configuration compound 1-1 (longer retention time):

[0246] MS m / z(ESI):539.0[M+1].

[0247] Chiral HPLC analysis: retention time 31.92 minutes, chiral purity: 99.1% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0248] 1 H NMR(500MHz,DMSO)δ7.61(brs,1H),7.54(brs,2H),7.52-7.46(m,3H),6.70-6.65(m,1H),5.13-5. 03(m,2H),3.89-3.54(m,6H),3.61(brs,4H),3.39-3.27(m,2H),2.40(brs,4H),0.85-0.77(m,2H).

[0249] Example 2

[0250] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(9-methoxy-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone

[0251]

[0252]

[0253] first step

[0254] tert-Butyl 1-(4-(morpholinylmethyl)phenyl)hydrazine-1-carboxylate 2b

[0255] Under argon, compound 4-(4-iodobenzyl)morpholine 2a (51 g, 168.24 mmol, prepared using the method disclosed in Example 17.1 on page 59 of patent application "WO200832191A2") and tert-butyl carbazate (23.347 g, 176.66 mmol, Shaoyuan) were dissolved in 400 mL of dimethyl sulfoxide and stirred for 10 minutes. Cuprous iodide (1.603 g, 8.42 mmol) was then added, and the mixture was heated to 50°C and stirred for 17 hours. 400 mL of water was added, and the aqueous phase was extracted with ethyl acetate (300 mL x 6). The combined organic phases were concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid prep instrument with eluent system A to obtain the title compound 2b (51 g, 98.6% yield).

[0256] MS m / z(ESI):308.1[M+1].

[0257] Step 2

[0258] 4-(4-Hydrazinobenzyl)morpholine 2c hydrochloride

[0259] Compound 2b (51 g, 165.91 mmol) was dissolved in 80 mL of methanol at 0°C. A solution of hydrogen chloride in 1,4-dioxane (350 mL, 4.0 M, Yanfeng Technology) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was concentrated under reduced pressure to obtain the crude hydrochloride salt of the title compound 2c (45.4 g), which was used directly in the next reaction without purification.

[0260] Step 3

[0261] 5-Methoxythiochroman-4-one 2e

[0262] 3-((3-Methoxyphenyl)thio)propanoic acid 2d (12 g, 56.53 mmol, prepared by the method disclosed in "Organic Letters, 2020, 22(3), 1155-1159") and sulfuric acid (40 mL) were added to a 100 mL single-necked flask and stirred at room temperature for 3 hours. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 2e (300 mg) with a yield of 2.73%.

[0263] Step 4

[0264] 2-(5-Methoxy-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 2f

[0265] Sodium ethoxide (1.44 g, 4.23 mmol, 20% content) was dissolved in 20 mL of toluene and cooled to 0°C. A solution of diethyl oxalate (463 mg, 3.166 mmol) in 20 mL of toluene was added dropwise, followed by compound 2e (410 mg, 2.11 mmol). The mixture was allowed to react at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and 100 mL of water was added to the residue. The mixture was extracted with dichloromethane (50 mL). The aqueous phase was adjusted to pH approximately 2 with 5 M hydrochloric acid solution and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 2f (900 mg), which was used directly in the next reaction without purification.

[0266] Step 5

[0267] 2-(5-methoxy-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 2g

[0268] Compound 2f (900 mg, 3.058 mmol) was dissolved in 30 mL of dichloromethane, and 3-chloroperoxybenzoic acid (1.2 g, 6.95 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified using a CombiFlash rapid prep instrument with eluent system B to obtain the title compound 2g (550 mg) in a yield of 55.1%.

[0269] Step 6

[0270] 9-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 2h

[0271] Compound 2g (550 mg, 1.68 mmol) was dissolved in 30 mL of ethanol, and the hydrochloride salt of compound 2c (384 mg) and glacial acetic acid (203 mg, 3.3804 mmol) were added. The reaction was stirred at 90°C for 2 hours. The mixture was concentrated under reduced pressure, slurried with ethanol, filtered, and the filter cake dried to obtain the title product 2h (700 mg) in an 83.4% yield.

[0272] Step 7

[0273] 9-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 2i

[0274] Compound 2h (700 mg, 1.41 mmol) was dissolved in 20 mL of tetrahydrofuran, and a 3 M sodium hydroxide solution (2.35 mL) was added. The mixture was stirred at room temperature for 4 hours. The pH of the reaction mixture was adjusted to approximately 2 with 5.0 M hydrochloric acid solution and concentrated under reduced pressure to obtain the title product 2i (1 g, 60% content), which was used directly in the next reaction without purification.

[0275] Step 8

[0276] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(9-methoxy-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone

[0277] Compound 2i (288 mg, 368.04 μmol, 60% content), compound 1b (50 mg, 368.75 μmol), HATU (168 mg, 441.84 μmol), and N,N-diisopropylethylamine (238 mg, 1.84 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 17 hours. 20 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a CombiFlash flash prep instrument with eluent system A to obtain the title product 2 (35 mg) in a 17.2% yield.

[0278] MS m / z(ESI):551.0[M+1].

[0279] 1 H NMR (500MHz, CDCl3) δ7.78-7.77(m,1H),7.59-7.56(m,1H),7.41-7.40(m,2H),7.39-7.34(m,2H),7.04-7.02(m,1H),5.00-4.69(m,2H),4.18-4. 04(m,1H),3.89-3.87(m,1H),3.80-3.64(m,7H),3.56-3.51(m,2H),3.5 0-3.49(m,1H),3.15-3.11(m,3H),2.50-2.48(m,4H),1.11-0.89(m,2H).

[0280] Example 3

[0281] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 3

[0282] ((1S,6R)-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 3-1

[0283] ((1R,6S)-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 3-2

[0284]

[0285] first step

[0286] 2-(8-Chloro-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 3b

[0287] Compound sodium ethoxide (62.0 g, 182.2 mmol, 20% content) was added to a 500 mL single-necked bottle, and 300 mL of a toluene solution of diethyl oxalate (19.9 g, 136.2 mmol) was added at 0°C, followed by the addition of compound 8-chlorothiochroman-4-one 3a (18.0 g, 90.6 mmol, prepared by the method disclosed in "Organic Letters, 2020, 22(3), 1155-1159"), and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, and the mixture was extracted with dichloromethane (200 mL × 2). The aqueous phase was adjusted to a pH of approximately 2 with 5 M hydrochloric acid solution, and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3b (13.2 g). The product was directly used for the next step without purification.

[0288] Step 2

[0289] 2-(8-Chloro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 3c

[0290] Compound 3b (10.80 g, 35.15 mmol) was dissolved in 150 mL of dichloromethane, and 3-chloroperoxybenzoic acid (16.2 g, 79.79 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified using a CombiFlash instrument with eluent System B to afford the title compound 3c (11.8 g) in a 98.7% yield.

[0291] Step 3

[0292] Ethyl 6-chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide 3d

[0293] Compound 3c (11.0 g, 33.3 mmol) was dissolved in 80 mL of ethanol, and the hydrochloride salt of compound 2c (9.0 g) and glacial acetic acid (20 mL) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, slurried with ethanol, filtered, and the filter cake dried to obtain the title product 3d (13.8 g) in an 83.1% yield.

[0294] Step 4

[0295] 6-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 3e

[0296] Compound 3d (12.7 g, 25.3 mmol) was dissolved in 100 mL of tetrahydrofuran, and a 3 M aqueous sodium hydroxide solution (5.5 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to approximately 2 with 5.0 M hydrochloric acid solution and concentrated under reduced pressure to obtain the crude title product 3e (15.1 g, 70% content), which was used directly in the next reaction without purification.

[0297] Step 5

[0298] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 3

[0299] ((1S,6R)-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 3-1

[0300] ((1R,6S)-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 3-2

[0301] Compound 3e (200 mg, 295.04 μmol, 70% content), compound 1b (48.1 mg, 354.5 μmol), HATU (146.1 mg, 384.1 μmol), and N,N-diisopropylethylamine (114.6 mg, 886.2 mmol) were dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 17 hours. 20 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a CombiFlash flash prep instrument with eluent system A to obtain the title product 3 (70 mg) in a 44.3% yield.

[0302] MS m / z(ESI):555.0[M+1].

[0303] 1H NMR(500MHz,DMSO-d6)δ7.65(m,1H),7.53-7.48(m,3H),7.45-7.42(m,2H),6.86-6.78(m,1H),5.14-5. 04(m,2H),3.93-3.54(m,10H),3.42-3.36(m,1H),3.32-3.11(m,1H),2.41(brs,4H),0.85-0.77(m,2H).

[0304] Compound 3 (70 mg, 0.13 mmol) was subjected to chiral separation (separation conditions: CHIRALPAK IG chiral preparative column, 150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)), flow rate: 1 mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title products 3-2 (26 mg) and 3-1 (28 mg).

[0305] Single configuration compound 3-2 (shorter retention time):

[0306] MS m / z(ESI):555.0[M+1].

[0307] Chiral HPLC analysis: retention time 36.29 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0308] 1 H NMR(500MHz,DMSO-d6)δ7.65(m,1H),7.48-7.53(m,3H),7.42-7.45(m,2H),6.78-6.86(m,1H),5.04-5. 14(m,2H),3.54-3.93(m,10H),3.36-3.42(m,1H),3.11-3.32(m,1H),2.41(brs,4H),0.77-0.85(m,2H).

[0309] Single configuration compound 3-1 (longer retention time):

[0310] MS m / z(ESI):555.0[M+1].

[0311] Chiral HPLC analysis: retention time 46.78 minutes, chiral purity: 99.1% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0312] 1 H NMR(500MHz,DMSO-d6)δ7.65(m,1H),7.48-7.53(m,3H),7.42-7.45(m,2H),6.78-6.86(m,1H),5.04-5. 14(m,2H),3.54-3.93(m,10H),3.36-3.42(m,1H),3.11-3.32(m,1H),2.41(brs,4H),0.77-0.85(m,2H).

[0313] Example 4

[0314] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-methoxy-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone

[0315]

[0316] first step

[0317] 2-(7-Methoxy-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 4b

[0318] Compound sodium ethoxide (19.267 g, 56.62 mmol, 20% content) was added to a 500 mL single-necked bottle, and 300 mL of a toluene solution of diethyl oxalate (6.207 g, 42.47 mmol) was added at 0°C. Then, 7-methoxythiochroman-4-one 4a (5.5 g, 28.31 mmol, prepared by the method disclosed in "Organic Letters, 2020, 22(3), 1155-1159") was added and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, and the mixture was extracted with dichloromethane (200 mL×2). The aqueous phase was adjusted to a pH of about 2 with 5 M hydrochloric acid solution, and extracted with ethyl acetate (200 mL×3). The combined organic phases were washed with brine (200 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 4b (8.3 g).

[0319] Step 2

[0320] 2-(7-Methoxy-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl 4c

[0321] Compound 4b (8.3 g, 28.20 mmol) was dissolved in 200 mL of dichloromethane, and m-chloroperbenzoic acid (12.166 g, 70.50 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a CombiFlash instrument with eluent System B to afford the title compound 4c (8.8 g) in a 95.6% yield.

[0322] Step 3

[0323] 7-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 4d

[0324] Compound 4c (8.8 g, 26.96 mmol) was dissolved in 200 mL of ethanol, and the hydrochloride salt of compound 2c (6.7 g) and glacial acetic acid (3.239 g, 53.93 mmol) were added. The reaction was stirred at 90°C for 2 hours. The mixture was spin-dried, slurried with ethanol, filtered, and the filter cake was dried to give the title product 4d (10.2 g) in a yield of 76.0%.

[0325] Step 4

[0326] 7-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 4e

[0327] Compound 4d (10.2 g, 20.5 mmol) was dissolved in 100 mL of tetrahydrofuran, and sodium hydroxide (1.0 M, 102.5 mL) was added and stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 2 with 5.0 M hydrochloric acid solution and concentrated under reduced pressure to obtain the title product 4e (16.3 g, 58.8% content).

[0328] Step 5

[0329] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-methoxy-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone

[0330] Compound 4e (150 mg, 319.48 μmol, 58.8%), compound 1b (52 mg, 383.5 μmol), HATU (146 mg, 383.97 μmol), and N,N-diisopropylethylamine (206 mg, 1.59 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 5 hours. 20 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified using a CombiFlash flash prep instrument with eluent system A to give the title product 4 (32 mg) in an 18.2% yield.

[0331] MS m / z(ESI):551.1[M+1].

[0332] 1 H NMR(500MHz,DMSO-d6)δ7.56-7.46(m,5H),7.18-7.15(m,1H),6.83-6.78(m,1H),5.00-4.87(m,2H),3.87-3 .78(m,3H),3.72-3.58(m,10H),3.38-3.36(m,1H),3.33-3.32(m,1H),2.43-2.42(m,4H),0.94-0.76(m,2H).

[0333] Example 5

[0334] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 5

[0335]

[0336] first step

[0337] 3-(o-Tolylthio)propionic acid 5b

[0338] Compound 2-methylthiophenol 5a (25.0 g, 201.2 mmol, Shaoyuan) and potassium carbonate (41.7 g, 301.9 mmol, Sinopharm) were dissolved in 200 mL of N,N-dimethylformamide (Sinopharm) and stirred at 60°C under nitrogen for 30 minutes. The mixture was cooled to room temperature, and 3-bromopropionic acid (32.3 g, 211.4 mmol, Admas) was added. Stirring at 60°C under nitrogen for another 3 hours was continued. 1000 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL x 2). The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid and extracted with ethyl acetate (400 mL x 2). The combined organic phases were washed sequentially with water (400 mL x 2) and saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title product 5b (39 g) in a 98% yield.

[0339] MS m / z(ESI):195.2[M-1].

[0340] Step 2

[0341] 8-Methylthiochroman-4-one 5c

[0342] Compound 5b (39 g, 198.6 mmol) was dissolved in concentrated sulfuric acid (200 mL) and stirred at 0°C for 2 hours. The reaction mixture was poured into 1000 mL of ice water and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with saturated brine (300 mL x 2) and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain the crude product. The residue was purified using a CombiFlash rapid prep instrument with eluent system B to obtain the title product 5c (15.5 g). Yield: 43%.

[0343] MS m / z(ESI):178.9[M+1].

[0344] Step 3

[0345] 2-(8-Methyl-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 5d

[0346] Sodium ethoxide (59 g, 173.93 mmol, Admas) was added to a 500 mL three-necked flask. Diethyl oxalate (19 g, 130.49 mmol, dissolved in 100 mL toluene) and compound 5c (15.5 g, 86.9 mmol, dissolved in 100 mL toluene) were added at 0°C and allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, and the mixture was extracted with dichloromethane (200 mL x 2). The aqueous phase was adjusted to a pH of approximately 2 with 5 M hydrochloric acid solution and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was spin-dried to give the title product 5d (24 g) in a 99.0% yield.

[0347] MS m / z(ESI):279.0[M+1].

[0348] Step 4

[0349] 2-(8-Methyl-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 5e

[0350] Compound 5d (24 g, 86.23 mmol) and m-chloroperbenzoic acid (29 g, 172.5 mmol, Wokai) were dissolved in 250 mL of dichloromethane and stirred for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a CombiFlash instrument with eluent System A to obtain the title compound 5e (26 g, 97.1% yield).

[0351] MS m / z(ESI):310.9[M+1].

[0352] Step 5

[0353] 6-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 5f

[0354] Compound 5e (15 g, 49.01 mmol), the hydrochloride salt of compound 2c (10 g), and acetic acid (5.9 g, 98.11 mmol, Shanghai test) were dissolved in 300 mL of anhydrous ethanol, heated to reflux, and stirred for 3 hours. 300 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (250 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified using a CombiFlash rapid prep instrument with eluent system A to obtain the title compound 5f (20 g, 86.9% yield).

[0355] MS m / z(ESI):482.0[M+1].

[0356] Step 6

[0357] 6-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 5g

[0358] Compound 5f (14 g, 29.07 mmol) was dissolved in 150 mL of tetrahydrofuran, and aqueous sodium hydroxide (58.2 mL, 2.5 M, homemade) was added and stirred for 4 hours. Concentrated hydrochloric acid was added to adjust the pH to approximately 3, and the mixture was concentrated under reduced pressure to obtain the crude title compound 5 g (21.2 g, 161.3% yield), which was used directly in the next reaction without purification.

[0359] MS m / z(ESI):454.0[M+1].

[0360] Step 7

[0361] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 5

[0362] Compound 5g (2 g, 2.64 mmol, 60%), compound 1b (358.7 mg, 2.64 mmol), HATU (1.8 g, 7.95 mmol), and N,N-diisopropylethylamine (2.4 g, 18.52 mmol) were dissolved in 60 mL of N,N-dimethylformamide and stirred at room temperature for 17 hours. 50 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified using a CombiFlash instrument with eluent system A to obtain the title product 5 (520 mg, 36.8% yield).

[0363] MS m / z(ESI):535.1[M+1].

[0364] 1 H NMR (500MHz, DMSO-d6): δ7.52-7.50(m,2H),7.41-7.36(m,4H),6.73-6.69(m,1H),5 .01-4.90(m,2H),3.94-3.52(m,12H),2.67(s,3H),2.40(t,4H),0.94-0.75(m,2H).

[0365] Examples 5-1, 5-2

[0366] (1S,6R)-2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 5-1

[0367] (1R,6S)-2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 5-2

[0368]

[0369] Compound 5 (520 mg, 0.22 mmol) was subjected to chiral separation (separation conditions: CHIRALPAK IG chiral preparative column, 150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to obtain the title products 5-2 (240 mg) and 5-1 (250 mg).

[0370] Single configuration compound 5-2 (shorter retention time):

[0371] MS m / z(ESI):535.1[M+1].

[0372] Chiral HPLC analysis: retention time 30.618 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0373] 1 H NMR(500MHz,DMSO)δ7.52-7.50(m,2H),7.41-7.35(m,4H),6.73-6.69(m,1H),5.01-4.90(m ,2H),3.94-3.52(m,11H),3.31-3.28(m,1H),2.67(s,3H),2.40(t,4H),0.94-0.75(m,2H).

[0374] Single configuration compound 5-1 (longer retention time):

[0375] MS m / z(ESI):535.1[M+1].

[0376] Chiral HPLC analysis: retention time 36.428 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0377] 1 H NMR(500MHz,DMSO)δ.52-7.50(m,2H),7.41-7.35(m,4H),6.73-6.69(m,1H),5.01-4.90(m ,2H),3.80-3.57(m,11H),3.31-3.28(m,1H),2.67(s,3H),2.40(t,4H),0.93-0.77(m,2H).

[0378] Example 6-1

[0379] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-fluoro-1-(4-(((R)-3-methylmorpholinyl)methyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 6-1

[0380]

[0381] first step

[0382] (R)-4-(4-Iodobenzyl)-3-methylmorpholine 6c

[0383] (R)-3-Methylmorpholine 6b (410 mg, 4.05 mmol, Admas) and N,N-diisopropylethylamine (700 mg, 5.42 mmol) were dissolved in 10 mL of acetonitrile. 1-(Bromomethyl)-4-iodobenzene 6a (1.2 g, 4.04 mmol) was added at room temperature and stirred for 17 hours. 200 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford the title product 6c (1.23 g, 95.9% yield).

[0384] MS m / z(ESI):317.9[M+1].

[0385] Step 2

[0386] tert-Butyl (R)-1-(4-((3-methylmorpholinyl)methyl)phenyl)hydrazinecarboxylate 6d

[0387] Compound 6c (1.23 g, 3.88 mmol), tert-butyl carbazate (550 mg, 4.15 mmol), cuprous iodide (40 mg, 210.03 μmol), and cesium carbonate (1.8 g, 5.52 mmol) were placed in 10 mL of dimethyl sulfoxide and heated at 50°C under a nitrogen atmosphere for 18 hours. 300 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to obtain 1.22 g of the title product 6d in a 97.8% yield.

[0388] Step 3

[0389] (R)-4-(4-Hydrazinobenzyl)-3-methylmorpholine 6e hydrochloride

[0390] Compound 6d (1.22 g, 3.79 mmol) was dissolved in 5 mL of methanol, and dioxane hydrochloride (4 M, 8.2 mL) was added. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated to dryness to obtain the crude title product 6e hydrochloride (839 mg). The product was directly used in the next reaction without purification.

[0391] Step 4

[0392] (R)-6-Fluoro-1-(4-((3-methylmorpholinyl)methyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 6f

[0393] Ethyl 2-(8-fluoro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetate (1.2 g, 3.82 mmol) and the hydrochloride salt of crude compound 6e (839 mg) were dissolved in 10 mL of ethanol, and acetic acid (450 mg, 7.50 mmol) was added. The mixture was heated under reflux for 3 hours. The reaction solution was concentrated, 200 mL of water was added, and the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to obtain the title product 6f (1.388 g, yield: 73.3%).

[0394] MS m / z(ESI):500.0[M+1].

[0395] Step 5

[0396] (R)-6-Fluoro-1-(4-((3-methylmorpholinyl)methyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 6g

[0397] Compound 6f (1.388 g, 2.78 mmol) was dissolved in 15 mL of tetrahydrofuran, and a 2.5 M aqueous sodium hydroxide solution (2.5 mL) was added. The mixture was heated at 60°C for 1 hour. The organic solvent was concentrated, and the pH of the residual aqueous phase was adjusted to neutral with 3 M hydrochloric acid. The aqueous phase was directly lyophilized to obtain the crude title compound 6g (1.86 g). This product was directly used in the next reaction without purification.

[0398] MS m / z(ESI):472.0[M+1].

[0399] Step 6

[0400] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-fluoro-1-(4-(((R)-3-methylmorpholinyl)methyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 6-1

[0401] Crude compound 6g (200 mg, 0.30 mmol), compound 1b (42 mg, 0.31 mmol), and HATU (170 mg, 0.45 mmol) were dissolved in 5 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (120 mg, 0.93 mmol, 0.15 mL) was added and stirred for 2 hours. The reaction was quenched by the addition of 150 mL of water. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride (50 mL x 3) and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent System A to obtain the title product 6-1 (78 mg, 47.5% yield).

[0402] MS m / z(ESI):553.0[M+1].

[0403] 1H NMR(500MHz, CDCl3)δ7.52-7.46(m,2H),7.40-7.35(m,2H),7.35-7.28(m,1H),7.19-7.13( m,1H),6.70-6.64(m,1H),5.06-4.83(m,2H),4.16-4.10(m,1H),4.10-3.96(m,1H),3.90-3 .83(m,1H),3.81-3.55(m,6H),3.48-3.42(m,0.5H),3.36-3.24(m,2H),3.18-3.12(m,0.5H ),2.67-2.61(m,1H),2.60-2.50(m,1H),2.32-2.24(m,1H),1.09(d,3H),0.94-0.79(m,2H).

[0404] Example 6-2

[0405] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-fluoro-1-(4-(((S)-3-methylmorpholinyl)methyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 6-2

[0406]

[0407] The synthetic route of Example 6-1 was adopted, and the first step raw material 6b was replaced with (S)-3-methylmorpholine to prepare the title compound 6-2.

[0408] MS m / z(ESI):553.0[M+H].

[0409] 1 H NMR (500MHz, CDCl3) δ7.53-7.45(m,2H),7.40-7.35(m,2H),7.35-7.28(m,1H),7.19-7.1 3(m,1H),6.70-6.62(m,1H),5.07-4.81(m,2H),4.16-4.06(m,1H),3.89-3.83(m,1H),3. 82-3.70(m,4H),3.70-3.55(m,2H),3.48-3.43(m,1H),3.36-3.24(m,2H),3.18-3.12(m, 1H),2.64(dt,1H),2.60-2.50(m,1H),2.32-2.22(m,1H),1.09(d,3H),0.93-0.81(m,2H).

[0410] Example 7

[0411] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 7

[0412]

[0413] first step

[0414] 3-((2-Methoxyphenyl)thio)propionic acid 7b

[0415] Compound 2-methoxythiophenol 7a (25.0 g, 178.31 mmol, Shaoyuan) and potassium carbonate (36.9 g, 267.50 mmol, Sinopharm) were dissolved in 200 mL of N,N-dimethylformamide (Sinopharm) and stirred at 60°C for 30 min under nitrogen. The mixture was cooled to room temperature, and 3-bromopropionic acid (28.6 g, 187.28 mmol, Admas) was added. Stirring at 60°C under nitrogen for 3 h was continued. 1000 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL x 2). The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid and extracted with ethyl acetate (400 mL x 2). The combined organic phases were washed sequentially with water (400 mL x 2) and saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title product 7b (37 g) in a 98% yield.

[0416] MS m / z(ESI):213.1[M+1].

[0417] Step 2

[0418] 8-Methoxythiochroman-4-one 7c

[0419] Compound 7b (37 g, 174.3 mmol) was dissolved in concentrated sulfuric acid (200 mL) and stirred at 0°C for 2 hours. The reaction mixture was poured into 1000 mL of ice water and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with saturated brine (300 mL x 2) and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain the crude product. The residue was purified using a CombiFlash rapid prep instrument with eluent system B to obtain the title product 7c (1.74 g). Yield: 4.3%.

[0420] MS m / z(ESI):194.9[M+1].

[0421] Step 3

[0422] 2-(8-Methoxy-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 7d

[0423] Sodium ethoxide (6.10 g, 17.92 mmol, Admas) was added to a 100 mL three-necked flask. Diethyl oxalate (1.97 g, 13.49 mmol, dissolved in 30 mL of toluene) and compound 7c (1.74 g, 8.95 mmol, dissolved in 30 mL of toluene) were added at 0°C and allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 80 mL of water was added to the residue, and the mixture was extracted with dichloromethane (80 mL x 2). The aqueous phase was adjusted to a pH of approximately 2 with 5 M hydrochloric acid solution and extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was spin-dried to give the title product 7d (2.6 g) in a 98.6% yield.

[0424] MS m / z(ESI):295.0[M+1].

[0425] Step 4

[0426] 2-(8-Methoxy-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 7e

[0427] Compound 7d (2.6 g, 8.83 mmol) and m-chloroperbenzoic acid (3.9 g, 19.47 mmol, Wokai) were dissolved in 250 mL of dichloromethane and stirred for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a CombiFlash instrument with eluent System A to obtain the title compound 7e (2.8 g, 97.1% yield).

[0428] MS m / z(ESI):326.9[M+1].

[0429] Step 5

[0430] 6-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 7f

[0431] Compound 7e (1.3 g, 3.98 mmol), the hydrochloride salt of compound 2c (825.7 mg), and acetic acid (478.4 mg, 7.96 mmol, Shanghai test) were dissolved in 60 mL of anhydrous ethanol, heated to reflux, and stirred for 3 hours. 60 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified using a CombiFlash rapid prep instrument with eluent system A to obtain the title compound 7f (1.63 g, 82.2% yield).

[0432] MS m / z(ESI):498.0[M+1].

[0433] Step 6

[0434] 6-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 7g

[0435] Compound 7f (1.63 g, 3.27 mmol) was dissolved in 30 mL of tetrahydrofuran, and aqueous sodium hydroxide solution (6.5 mL, 2.5 M, self-prepared) was added and stirred for 4 hours. Concentrated hydrochloric acid was added to adjust the pH to approximately 3, and the mixture was concentrated under reduced pressure to obtain the crude title compound 7g (2.4 g, 156.0% yield), which was used directly in the next step without purification.

[0436] MS m / z(ESI):470.0[M+1].

[0437] Step 7

[0438] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 7

[0439] Compound 7g (0.3 g, 0.38 mmol, 60%), compound 1b (135.6 mg, 0.38 mmol), HATU (270.59 mg, 1.15 mmol), and N,N-diisopropylethylamine (297.29 mg, 2.30 mmol) were dissolved in 30 mL of N,N-dimethylformamide and stirred at room temperature for 17 hours. 50 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified using a CombiFlash instrument with eluent system A to obtain the title product 7 (129 mg, 61.1% yield).

[0440] MS m / z(ESI):551.1[M+1].

[0441] 1 H NMR (500MHz, DMSO-d6): δ7.53-7.39(m,5H),7.25(d,1H),6.40-6.36(m,1H),4.92-4.82(m,2H),3.9 1(s,3H),3.79-3.52(m,10H),3.41-3.37(m,1H),3.32-3.28(m,1H),2.41(s,4H),0.95-0.75(m,2H).

[0442] Examples 7-1, 7-2

[0443] ((1S,6R)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 7-1

[0444] ((1R,6S)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 7-2

[0445]

[0446] Compound 7 (102 mg, 0.19 mmol) was subjected to chiral separation (separation conditions: CHIRALPAK IG chiral preparative column, 150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol = 80 / 20 (V / V), flow rate: 1 mL / min), and the corresponding components were collected and concentrated under reduced pressure to obtain the title products 7-1 (23 mg) and 7-2 (28 mg).

[0447] Single configuration compound 7-2 (shorter retention time):

[0448] MS m / z(ESI):551.1[M+1].

[0449] Chiral HPLC analysis: retention time 35.649 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0450] 1 H NMR (500MHz, DMSO-d6): δ7.52-7.39(m,5H),7.25(d,1H),6.41-6.37(m,1H),4.94-4.83(m,2H),3.9 1(s,3H),3.80-3.52(m,10H),3.41-3.37(m,1H),3.32-3.28(m,1H),2.41(s,4H),0.93-0.75(m,2H).

[0451] Single configuration compound 7-1 (longer retention time):

[0452] MS m / z(ESI):551.1[M+1].

[0453] Chiral HPLC analysis: retention time 61.556 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol / diethylamine = 80 / 19.98 / 0.02 (v / v / v)).

[0454] 1 H NMR (500MHz, DMSO-d6): δ7.52-7.39(m,5H),7.25(d,1H),6.41-6.37(m,1H),4.94-4.83(m,2H),3.9 1(s,3H),3.80-3.52(m,10H),3.41-3.37(m,1H),3.32-3.28(m,1H),2.41(s,4H),0.94-0.75(m,2H).

[0455] Example 8

[0456] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-6-(trifluoromethyl)-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 8

[0457]

[0458] first step

[0459] 3-((2-(Trifluoromethyl)phenyl)thio)propanoic acid 8b

[0460] 2-(Trifluoromethyl)thiophenol 8a (10.4 g, 58.3 mmol, TCI) was dissolved in N,N-dimethylformamide (60 mL), potassium carbonate (16.1 g, 116.5 mmol) was added, and the mixture was stirred at 60°C for 30 minutes. After cooling, bromopropionic acid (9.8 g, 64.3 mmol) was added, and stirring was continued at 60°C for 3 hours. The mixture was cooled, poured into water, and the pH was adjusted to 2 with 2M hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified using a CombiFlash instrument with eluent system B to obtain the title compound 8b (11.0 g) in a 75.3% yield.

[0461] Step 2

[0462] 8-(Trifluoromethyl)thiochroman-4-one 8c

[0463] Compound 8b (11.0 g, 46.5 mmol) was added to concentrated sulfuric acid (150 mL) and stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and stirred until uniform. Filtered and washed with water, the solid was dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified using a CombiFlash rapid prep instrument with eluent A to obtain the title compound 8c (8.0 g) in a 71.8% yield.

[0464] Step 3

[0465] 2-(8-(Trifluoromethyl)-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 8d

[0466] Sodium ethoxide (23.5 g, 69.1 mmol, 20% content) was added to a 500 mL single-necked flask. A 200 mL solution of diethyl oxalate (7.6 g, 51.7 mmol) in toluene was added at 0°C, followed by compound 8c (8.0 g, 34.5 mmol). The mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and 300 mL of water was added to the residue. The mixture was extracted with dichloromethane (100 mL x 2). The aqueous phase was adjusted to pH approximately 2 with 5 M hydrochloric acid solution and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound 8d (9.1 g), which was used directly in the next step.

[0467] Step 4

[0468] 2-(8-(Trifluoromethyl)-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 8e

[0469] Compound 8d (9.1 g, 27.2 mmol) was dissolved in 150 mL of dichloromethane, and 3-chloroperoxybenzoic acid (11.6 g, 57.2 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified using a CombiFlash instrument with eluent System B to afford the title compound 8e (9.8 g) in a 99.3% yield.

[0470] Step 5

[0471] Ethyl 6-(trifluoromethyl)-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide 8f

[0472] Compound 8e (9.8 g, 26.9 mmol) was dissolved in 80 mL of ethanol, and the hydrochloride salt of compound 2c (7.0 g) and glacial acetic acid (20 mL) were added. The reaction was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure, slurried with ethanol, filtered, and the filter cake dried to obtain the title product 8f (8.0 g) in a yield of 55.5%.

[0473] Step 6

[0474] 8g of 6-(trifluoromethyl)-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide

[0475] Compound 8f (8.0 g, 14.9 mmol) was dissolved in 100 mL of tetrahydrofuran, and a 3 M aqueous sodium hydroxide solution (5.5 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to approximately 2 with 5.0 M hydrochloric acid solution and concentrated under reduced pressure to obtain 8 g (10.5 g, 70% content) of the crude title product, which was used directly in the next reaction without purification.

[0476] Step 7

[0477] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-6-(trifluoromethyl)-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 8

[0478] Crude compound 8g (200 mg, 295.04 μmol, 70% content), compound 1b (46.1 mg, 339.5 μmol), HATU (137.1 mg, 360.1 μmol), and N,N-diisopropylethylamine (179.6 mg, 1.4 mmol) were dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 17 hours. 20 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a CombiFlash flash prep instrument with eluent system A to obtain the title product 8 (130 mg) in an 80.5% yield.

[0479] MS m / z(ESI):588.8[M+1].

[0480] 1H NMR(500MHz,DMSO-d6)δ8.01(d,1H),7.75(t,1H),7.53-7.50(m,2H),7.53-7.42(m,2H),7.27-7.17(m,1H) ,5.15-5.05(m,2H),3.59-3.54(m,10H),3.43-3.39(m,1H),3.30(s,1H),2.40(brs,4H),0.88-0.78(m,2H).

[0481] Example 9

[0482] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 9

[0483]

[0484] first step

[0485] 2-(7-Chloro-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 9b

[0486] Sodium ethoxide (62.0 g, 182.2 mmol, 20% content) was added to a 500 mL single-necked bottle, and 300 mL of a toluene solution of diethyl oxalate (19.9 g, 136.2 mmol) was added at 0°C. Then, 7-chlorothiochroman-4-one 9a (18.0 g, 90.6 mmol, prepared according to "Organic Letters, 2020, 22(3), 1155-1159") was added and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, and the mixture was extracted with dichloromethane (200 mL × 2). The aqueous phase was adjusted to a pH of about 2 with 5 M hydrochloric acid solution, and then extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9b (13.7 g). The product was directly used in the next step without purification.

[0487] Step 2

[0488] 2-(7-Chloro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 9c

[0489] Compound 9b (11.80 g, 36.15 mmol) was dissolved in 150 mL of dichloromethane, and 3-chloroperoxybenzoic acid (17.2 g, 81.79 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified using a CombiFlash instrument with eluent System B to obtain the title compound 9c (12.3 g) in a 98.3% yield.

[0490] Step 3

[0491] 7-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 9d

[0492] Compound 9c (11.3 g, 33.6 mmol) was dissolved in 80 mL of ethanol, and the hydrochloride salt of compound 2c (9.0 g) and glacial acetic acid (20 mL) were added. The reaction was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure, slurried with ethanol, filtered, and the filter cake dried to obtain the title product 9d (13.9 g) in an 83.2% yield.

[0493] Step 4

[0494] 7-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 9e

[0495] Compound 9d (13.9 g, 28.3 mmol) was dissolved in 100 mL of tetrahydrofuran, and a 3 M aqueous sodium hydroxide solution (5.5 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to approximately 2 with 5.0 M hydrochloric acid solution and concentrated under reduced pressure to obtain the title product 9e (16.1 g), which was used directly in the next reaction without purification.

[0496] Step 5

[0497] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 9

[0498] Crude compound 9e (200 mg, 295.04 μmol, 70% content), compound 1b (48.1 mg, 354.5 μmol), HATU (146.1 mg, 384.1 μmol), and N,N-diisopropylethylamine (114.6 mg, 886.2 mmol) were dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 17 hours. 20 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with water (20 mL x 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a CombiFlash flash prep instrument with eluent system A to obtain the title product 9 (52 mg) in a 33.1% yield.

[0499] MS m / z(ESI):554.8[M+1].

[0500] 1 H NMR(500MHz,DMSO-d6)δ8.01(d,1H),7.73-7.71(m,1H),7.60-7.55(m,2H),7.51-7.49(m,2H),6.90-6.85(m,1H) ,5.08-4.97(m,2H),3.91-3.55(m,10H),3.40-3.36(m,1H),3.31-3.29(m,1H),2.42(brs,4H),0.85-0.76(m,2H).

[0501] Example 10

[0502] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 10

[0503]

[0504]

[0505] first step

[0506] 3-(m-Tolylthio)propionic acid 10b

[0507] 3-Methylthiophenol 10a (10 g, 80.5 mmol, Adamas) was dissolved in 100 ml of N,N-dimethylformamide, and potassium carbonate (16 g, 115.7 mmol) was added. 3-Bromopropionic acid was then added with stirring at room temperature, and the mixture was stirred for 2 hours. The mixture was quenched with 500 ml of water, separated, and the aqueous phase was extracted with ethyl acetate (80 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude title compound 10b (8.94 g, 56.5% yield), which was used directly in the next reaction without purification.

[0508] MS m / z(ESI):195.0[M-1].

[0509] Step 2

[0510] 7-Methylthiochroman-4-one 10c

[0511] Crude compound 10b (8.94 g, 45.5 mmol) was dissolved in 100 mL of concentrated sulfuric acid and stirred at room temperature for 3 hours. The reaction mixture was carefully poured into 500 g of ice water to quench the mixture. The layers were separated, and the aqueous phase was extracted with ethyl acetate (80 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography using solvent System B to obtain the title compound 10c (5.17 g, 63.7% yield).

[0512] 1 H NMR (500MHz, CDCl3) δ7.86(d,1H),7.18(d,1H),7.04(dd,1H),3.32-3.25(m,2H),2.90-2.82(m,2H),2.30(s,3H).

[0513] Step 3

[0514] 2-(7-methyl-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 10e

[0515] A solution of sodium ethoxide in ethanol (20 g, 58.78 mmol, 20% content) was added to a single-necked flask and cooled in an ice bath. Diethyl oxalate (4.5 g, 30.79 mmol, dissolved in 50 mL of toluene) was then added, followed by the addition of compound 10c (5.17 g, 29.00 mmol, dissolved in 50 mL of toluene) with stirring. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated and quenched by the addition of 200 mL of water. The pH was adjusted to neutral with 3 M saline solution. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude title compound 10e (7.87 g, 97.5% yield), which was directly used in the next step without purification.

[0516] MS m / z(ESI):279.0[M+1].

[0517] Step 4

[0518] 2-(7-Methyl-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 10f

[0519] Compound 10e (7.78 g, 28.28 mmol) was dissolved in 240 mL of dichloromethane. m-Chloroperbenzoic acid (14 g, 68.96 mmol) was added portionwise under ice-cooling. The mixture was stirred at room temperature for 3 hours. Insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by column chromatography using System A to obtain the title compound 10f (6.88 g, 78.2% yield).

[0520] MS m / z(ESI):310.9[M+1].

[0521] Step 5

[0522] 7-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 10g

[0523] Compound 10f (6.88 g, 22.17 mmol) and the hydrochloride salt of intermediate 2c (4.5 g) were dissolved in 150 mL of ethanol. Acetic acid (2.5 g, 41.63 mmol) was added and the mixture was stirred at reflux for 6 hours. After the reaction mixture cooled to room temperature, it was filtered and the filter cake was vacuum-dried to obtain 10 g (14.7 g) of the title product, which was carried on to the next step without further purification.

[0524] MS m / z(ESI):482.2[M+1].

[0525] Step 6

[0526] 7-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 10h

[0527] Compound 10g (5g, 10.38mmol) was dissolved in 60mL of tetrahydrofuran, and aqueous sodium hydroxide solution (2.5M, 10mL) was added. The mixture was heated and stirred at 60°C for 1 hour. After the reaction mixture cooled to room temperature, the pH was adjusted to neutral with 3M hydrochloric acid. The organic solution was concentrated, and the remaining aqueous phase was lyophilized to obtain the crude title product 10h (9g). This product was directly used in the next reaction without purification.

[0528] MS m / z(ESI):452.1[M-1].

[0529] Step 7

[0530] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(7-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 10

[0531] Crude compound 10h (200 mg, 0.22 mmol), compound 1b (30 mg, 0.22 mmol), and HATU (100 mg, 0.26 mmol) were dissolved in 5 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (140 mg, 1.00 mmol, 0.18 mL) was added and stirred for 2 hours. The reaction was quenched by the addition of 150 mL of water. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride (50 mL x 3) and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent System A to obtain the title product 10 (25 mg, 21.5% yield).

[0532] MS m / z(ESI):535.1[M+H].

[0533] 1 H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.58-7.51(m,2H),7.47(d,2H),7.42-7.35(m,1H),6.78-6.70(m,1H),5.00-4.83(m,2H),3 .93-3.84(m,1H),3.82-3.51(m,11H),3.42-3.36(m,1H),3.29(s,1H),3.10-3.03(m,1H),2.44-2.36(m,4H),0.88-0.72(m,2H).

[0534] Examples 10-1, 10-2

[0535] ((1R,6S)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl(7-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 10-1

[0536] ((1S,6R)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl(7-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 10-2

[0537]

[0538] Compound 10 (102 mg, 0.19 mmol) was subjected to chiral separation (separation conditions: CHIRALPAK IG chiral preparative column, 150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol = 80 / 20 (V / V), flow rate: 1 mL / min), and the corresponding components were collected and concentrated under reduced pressure to obtain the title products 10-1 (23 mg) and 10-2 (28 mg).

[0539] Single configuration compound 10-1 (shorter retention time):

[0540] MS m / z(ESI):535.1[M+1].

[0541] Chiral HPLC analysis: retention time 32.306 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol = 20 / 80 (v / v / v)).

[0542] 1 H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.58-7.51(m,2H),7.47(d,2H),7.42-7.35(m,1H),6.78-6.70(m,1H),5.00-4.83(m,2H),3 .93-3.84(m,1H),3.82-3.51(m,11H),3.42-3.36(m,1H),3.29(s,1H),3.10-3.03(m,1H),2.44-2.36(m,4H),0.88-0.72(m,2H).

[0543] Single configuration compound 10-2 (longer retention time):

[0544] MS m / z(ESI):535.1[M+1].

[0545] Chiral HPLC analysis: retention time 40.111 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: n-hexane / ethanol = 20 / 80 (v / v / v)).

[0546] 1H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.58-7.51(m,2H),7.47(d,2H),7.42-7.35(m,1H),6.78-6.70(m,1H),5.00-4.83(m,2H),3 .93-3.84(m,1H),3.82-3.51(m,11H),3.42-3.36(m,1H),3.29(s,1H),3.10-3.03(m,1H),2.44-2.36(m,4H),0.88-0.72(m,2H).

[0547] Example 11

[0548] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 11

[0549]

[0550] first step

[0551] 3-((3-chloro-2-fluorophenyl)thio)propanoic acid 11b

[0552] 3-Chloro-2-fluorothiophenol 11a (8 g, 49.20 mmol, Wuxi Kehua) was dissolved in 100 mL of N,N-dimethylformamide, and potassium carbonate (8.840 g, 63.96 mmol) was added. The mixture was stirred at 60°C for 30 minutes, followed by 3-bromopropionic acid (8.279 g, 54.12 mmol, Adamas), and stirred at 60°C for 2 hours. The mixture was quenched with 500 mL of water and extracted with ethyl acetate (200 mL x 1). The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid and then extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude title compound 11b (11.166 g, 96.7% yield), which was used directly in the next step without purification.

[0553] Step 2

[0554] 7-Chloro-8-fluorothiochroman-4-one 11c

[0555] Crude compound 11b (11.116 g, 47.37 mmol) was dissolved in 100 mL of concentrated sulfuric acid and stirred at room temperature for 3 hours. The reaction mixture was carefully poured into 500 mL of ice water to quench the mixture. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound 11c (8.731 g, 85.1% yield), which was used directly in the next step without further purification.

[0556] Step 3

[0557] 2-(7-chloro-8-fluoro-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 11d

[0558] To a single-necked flask, sodium ethoxide in ethanol (27.423 g, 80.60 mmol, 20%, TCI) and 125 mL of toluene were added. The mixture was cooled in an ice bath, followed by diethyl oxalate (8.834 g, 60.45 mmol, Shanghai test) and compound 11c (8.731 g, 40.30 mmol) under stirring. The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated and quenched by the addition of 600 mL of water. The pH was adjusted to approximately 3 with concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate (250 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 11d (11.919 g, 93.4% yield).

[0559] MS m / z(ESI):316.9[M+1].

[0560] Step 4

[0561] 2-(7-chloro-8-fluoro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 11e

[0562] Compound 11d (11.919 g, 37.63 mmol) was dissolved in 130 mL of dichloromethane. m-Chloroperbenzoic acid (19.100 g, 94.08 mmol) was added portionwise under ice-cooling. The mixture was stirred at room temperature for 17 hours. Insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by column chromatography using System A to obtain the title compound 11e (11.5 g, yield: 87.6%).

[0563] MS m / z(ESI):347.0[M-1].

[0564] Step 5

[0565] Ethyl 7-chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide 11f

[0566] Compound 11e (11.5 g, 32.98 mmol) and the hydrochloride salt of compound 2c (10.024 g) were dissolved in 250 mL of ethanol, and acetic acid (3.961 g, 65.96 mmol) was added. The mixture was stirred at reflux for 3 hours. 300 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (250 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 11f (16 g, yield: 93.3%). The product was directly used in the next reaction without purification.

[0567] MS m / z(ESI):520.0[M+1].

[0568] Step 6

[0569] 7-Chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 11g

[0570] Crude compound 11f (16 g, 30.77 mmol) was dissolved in 250 mL of tetrahydrofuran, and aqueous sodium hydroxide (2.5 M, 62 mL) was added. The mixture was stirred at room temperature for 4 hours. The pH of the reaction solution was adjusted to approximately 3 with 3 M hydrochloric acid and concentrated under reduced pressure to afford the crude title product 11 g (15 g, 99.1% yield). This product was directly used in the next reaction without purification.

[0571] MS m / z(ESI):491.9[M+1].

[0572] Step 7

[0573] (2-Oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 11

[0574] Crude compound 11g (558 mg, 0.58 mmol), compound 1b (80 mg, 0.59 mmol), and HATU (264 mg, 0.69 mmol, Shaoyuan) were dissolved in 25 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (374 mg, 2.89 mmol) was added. The mixture was stirred and reacted for 17 hours. The reaction was quenched by the addition of 50 mL of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent System A to obtain the title product 11 (77.2 mg, yield: 23.3%).

[0575] MS m / z(ESI):573.0[M+1].

[0576] 1 H NMR(500MHz,DMSO-d6)δ7.86-7.83(m,1H),7.53-7.47(m,4H),6.71-6.66 (m,1H),5.17-5.07(m,2H),4.04-3.58(m,11H),2.50-2.41(m,5H),0.93-0.78(m,2H).

[0577] Example 12

[0578] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(9-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 12

[0579]

[0580] first step

[0581] 2-(5-methyl-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 12a

[0582] A single-necked flask was charged with an ethanolic solution of sodium ethoxide (13 g, 38.21 mmol, 20% content) and cooled in an ice bath. Diethyl oxalate (3.0 g, 20.53 mmol, dissolved in 50 mL of toluene) was then added. Compound 10d (3.38 g, 18.93 mmol, dissolved in 50 mL of toluene) was then added with stirring and stirred at room temperature for 18 hours. The reaction solution was concentrated and quenched by the addition of 200 mL of water. The pH was adjusted to neutral with 3 M saline solution. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 12a (3.66 g, 69.56% yield), which was directly used in the next reaction without purification.

[0583] MS m / z(ESI):279.0[M+1].

[0584] Step 2

[0585] 2-(5-methyl-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 12b

[0586] Compound 12a (3.66 g, 13.17 mmol) was dissolved in 50 mL of dichloromethane. m-Chloroperbenzoic acid (6 g, 29.55 mmol, 85% content) was added portionwise under ice-cooling. The mixture was stirred at room temperature for 3 hours. Insoluble matter was filtered off, the filtrate was concentrated, and the residue was purified by column chromatography using System A to obtain the crude title compound 12b (7.3 g, crude product).

[0587] MS m / z(ESI):310.9[M+1].

[0588] Step 3

[0589] 9-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 12c

[0590] Crude compound 12b (7.3 g, 12.94 mmol) and the hydrochloride salt of intermediate 2c (3.6 g) were dissolved in 50 mL of ethanol. Acetic acid (1.5 g, 24.98 mmol) was added and the mixture was stirred at reflux for 6 hours. After the reaction mixture cooled to room temperature, it was filtered and the filter cake was vacuum-dried to obtain the title product 12c (6.8 g). This product was directly used in the next reaction without further purification.

[0591] MS m / z(ESI):482.2[M+1].

[0592] Step 4

[0593] 9-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 12d

[0594] Crude compound 12c (1.35 g, 1.54 mmol) was dissolved in 15 mL of tetrahydrofuran, and aqueous sodium hydroxide solution (2.5 M, 3 mL) was added. The mixture was heated and stirred at 60°C for 1 hour. After the reaction mixture cooled to room temperature, the pH was adjusted to neutral with 3 M hydrochloric acid. The organic solution was concentrated, and the remaining aqueous phase was lyophilized to obtain the crude title product 12d (2.2 g). This product was directly used in the next reaction without purification.

[0595] MS m / z(ESI):452.1[M-1].

[0596] Step 5

[0597] 2-Oxa-5-azabicyclo[4.1.0]hept-5-yl(9-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 12

[0598] Crude compound 12d (200 mg, 0.22 mmol), compound 1b (40 mg, 0.29 mmol), and HATU (160 mg, 0.42 mmol) were dissolved in 5 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (140 mg, 1.00 mmol, 0.18 mL) was added and stirred for 2 hours. The reaction was quenched by the addition of 150 mL of water. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride (50 mL x 3) and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent System A to obtain the title product 12 (62 mg, 43.8% yield).

[0599] MS m / z(ESI):535.1[M+H].

[0600] 1 H NMR(500MHz,DMSO-d6)δ7.90(d,1H),7.64(t,1H),7.54(d,1H),7.45(d,2H),7.28(s,2H),4.86(s,2H ),3.84-3.48(m,10H),3.42-3.36(m,1H),3.30(s,1H),2.37(s,4H),1.62(s,3H),0.96-0.76(m,2H).

[0601] Comparative Example A1

[0602] (2H-Benzo[b][1,4]oxazin-4(3H)-yl)(6-fluoro-1-(4-(morpholinomethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone A1

[0603]

[0604]

[0605] Compound 1a and 3,4-dihydro-2H-benzo[b][1,4]oxazine A1a (115 mg, 0.85 mmol, Adamas) were added to N,N-dimethylformamide (20 mL). N,N-diisopropylethylamine (423 mg, 3.27 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (498 mg, 1.31 mmol, HATU) were added sequentially with stirring. The mixture was stirred at room temperature overnight. 50 mL of water was added and the mixture was extracted three times with a mixture of dichloromethane and methanol (v:v = 8:1). The organic phases were combined, washed sequentially with water and saturated sodium chloride solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to obtain the title compound A1 (32 mg, 8.5% yield).

[0606] MS m / z(ESI):575.0[M+1].

[0607] 1 H NMR (500MHz, DMSO-d6): δ7.51(d,2H),7.39-7.32(m,3H),7.20-7.06(m,3H),6.94-6.90(m ,2H),6.69(d,1H),4.79(s,2H),4.43-4.36(m,4H),3.74(t,4H),3.68(s,2H),2.50(t,4H).

[0608] Test example:

[0609] Biological evaluation

[0610] Test Example 1: Inhibitory activity and selectivity test of the disclosed compounds against PI3Kδ enzyme

[0611] 1. Experimental purpose:

[0612] The purpose of this experiment is to test the inhibitory effect and selectivity of compounds on PI3Kδ enzymatic activity. 50 The size was used to evaluate the in vitro activity of the compounds.

[0613] 2. Experimental Principle:

[0614] In this experiment, ADP-Glo was used TMIn the Kinase Assay Kit, the enzyme phosphorylates the substrate and produces ADP. ADP-Glo Reagent is added to remove unreacted ATP from the reaction system, and the Kinase Detection Reagent detects the ADP produced. In the presence of the compound, the inhibition rate is calculated by measuring the signal.

[0615] 3. Experimental Materials

[0616] 1. Instruments

[0617] Instrument name Supplier model centrifuge Eppendorf 5430 microplate reader Perkin Elmer Envision, SN.1050214 Echo 550 Labcyte Echo 550

[0618] 2. Reagents and consumables

[0619] Reagent name Supplier Item No. PIK3CD / PIK3R1 Carna 11-103 PI103 selleckchem S1038 DMSO Sigma D8418-1L 384-well white plate PerkinElmer 6007290

[0620] IV. Experimental Methods

[0621] The test compound was tested at a starting concentration of 10,000 nM, followed by 3-fold dilutions to 11 concentrations in duplicate. A gradient dilution was performed in a 384-well plate to yield 11 solutions with a final concentration of 100 times. 50 nL was transferred to the compound wells of the 384-well plate using an Echo; 50 nL of DMSO was added to the negative and positive control wells. A kinase solution with a final concentration of 2 times was prepared using 1× kinase buffer. 2.5 μL of the kinase solution with a final concentration of 2 times was added to the compound wells and positive control wells; 2.5 μL of 1× kinase buffer was added to the negative control wells. The mixture was centrifuged at 1,000 rpm for 30 seconds, shaken to mix, and incubated at room temperature for 10 minutes. A mixed solution of ATP and substrate P1P2 with a final concentration of 2 times was prepared using 1× kinase buffer. The reaction was initiated by adding 2.5 μL of the mixed solution of ATP and substrate with a final concentration of 2 times. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 120 minutes. Add 5 μL of ADP-Glo reagent, centrifuge at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 40 minutes. Add 10 μL of kinase assay reagent, centrifuge at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 30 minutes. Read the luminescence (RLU) values using an Envision microplate reader.

[0622] The structure of compound B is:

[0623]

[0624] Compound B was prepared using the method disclosed in "Example 339 on page 339 of the specification of patent CN102695710B".

[0625] 5. Data Analysis

[0626] The IC of the inhibitory activity of the compounds was calculated using Graphpad Prism software 50 The results are shown in Table 1 below.

[0627] Table 1 Inhibitory and selective activity data of the disclosed compounds against PI3Kδ enzyme (unit: nM)

[0628]

[0629]

[0630] Conclusion: The disclosed compounds have strong inhibitory activity and selectivity against PI3Kδ enzyme.

[0631] Test Example 2: Proliferation inhibition test of the disclosed compounds on TMD-8 cells

[0632] 1. Experimental purpose:

[0633] The purpose of this experiment is to test the inhibitory effect of compounds on TMD-8 cell proliferation activity. 50 The size was used to evaluate the in vitro activity of the compounds.

[0634] 2. Experimental Principle:

[0635] ATP is an indicator of the metabolism of living cells. Luminescent Cell Viability Assay is a homogeneous detection method for detecting the number of living cells by quantitatively measuring ATP.

[0636] 3. Experimental instruments, materials and reagents

[0637] Experimental instruments:

[0638] (1) Microplate reader (BMG, PHERAstar)

[0639] Experimental Materials:

[0640] (1) 96-well plate (Corning, 3903)

[0641] (2) 96-well U-bottom plate (Corning, 3795)

[0642] (3)TMD-8(ETERNITY BIOSCIENCE INC.)

[0643] Experimental reagents:

[0644] (1) Fetal bovine serum (Gibco, 10099-141)

[0645] (2) RPMI 1640 culture medium (Hyclone, SH30809.01B)

[0646] (3) Luminescent cell viability assay (Promege, G7573)

[0647] (4)PBS (Hyclone, SH30256.01)

[0648] (5) 0.25% trypsin-EDTA (1x), phenol red (Invitrogen, 25200-072)

[0649] 4. Experimental methods:

[0650] 180 μL of TMD-8 cell suspension was added to a 96-well cell culture plate, with a plate count of 2,000 cells / well. The culture medium was RPMI1640 with 10% FBS. Only 200 μL of RPMI1640 with 10% FBS was added to the periphery of the 96-well plate. The plate was incubated in an incubator for 24 hours (37°C, 5% CO₂). The next day, 20 μL of the prepared compound at various concentrations (initial concentration: 20 μM, three-fold dilutions, for a total of nine concentrations) was added to the plate. The plate was incubated in an incubator for 6 days (37°C, 5% CO₂). After 6 days, 100 μL of mixed Cell Titer-Glo (10 mL of buffer added to the corresponding brown bottle containing substrate) was added to each well, mixed by vortexing, and allowed to stand at room temperature for 10 minutes. The chemiluminescence signal was read in PHERAstar, and the data were processed using GraphPad software.

[0651] 5. Experimental Data

[0652] The inhibitory activity of the disclosed compounds on TMD-8 cell proliferation can be determined by the above test, and the measured IC 50 See Table 2 for values.

[0653] Table 2 IC values of the disclosed compounds for inhibition of TMD-8 cell proliferation 50

[0654] Example No. <![CDATA[IC 50 / nM]]> Maximum inhibition (%) 1 414 100.96 1-2 299.6 101.2 3 512.6 101.5 3-2 192.7 101.4 4 295.7 101.4 5-2 485 100.8 7 29.2 101.7 11 258.4 101.4 Comparative Example A1 3208.0 69.2

[0655] Conclusion: The disclosed compounds have good inhibitory activity on TMD-8 cell proliferation.

Claims

1. A compound represented by general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof: in R 1 the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; R 2 and R 4 the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; R 3 the same or different, each independently selected from hydrogen, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 alkyl; R 10 the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; R 11 the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; R 12 the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; m is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, 4, 5, or 6.

2. The compound of general formula (II) according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

3. The compound of general formula (II) according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 All are hydrogen.

4. The compound of general formula (II) according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl.

5. The compound of general formula (II) according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 10 For hydrogen.

6. The compound of general formula (II) according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 11 For hydrogen.

7. The compound of general formula (II) according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 12 For hydrogen.

8. A compound represented by general formula (II) according to any one of claims 1 to 7, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:

9. A method for preparing the compound of general formula (II) according to claim 1 or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, the method comprising the following steps: The compound of general formula (IIA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is reacted with the compound of general formula (IIB) or a pharmaceutically acceptable salt thereof to obtain the compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, where R 1 -R 4 、R 10 -R 12 , q, u, w and m are as defined in claim 1.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (II) according to any one of claims 1 to 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition according to claim 10 , wherein the excipient is a diluent.

12. Use of the compound represented by general formula (II) according to any one of claims 1 to 8, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for inhibiting PI3Kδ.

13. Use of a compound of formula (II) according to any one of claims 1 to 8, or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating and / or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases.

14. The method of claim 13, wherein the cancer and related diseases are selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma.

15. The use according to claim 14, wherein the leukemia is selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia; and / or the lymphoma is selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma and diffuse large B-cell lymphoma; and / or the lung cancer is non-small cell lung cancer or small cell lung cancer; and / or the myeloma is multiple myeloma (MM); and / or the liver cancer is hepatocellular carcinoma; and / or the head and neck tumor is head and neck squamous cell carcinoma; and / or the sarcoma is osteosarcoma or soft tissue sarcoma; and / or the colorectal cancer is colon cancer or rectal cancer.

16. The compound of general formula (II) according to any one of claims 1 to 8, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 10, in the preparation of a pharmaceutical composition for treating and / or preventing asthma, rheumatoid arthritis, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behçet's disease, celiac disease, anti-glutaminase, Chagas' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis. Use of the present invention in a drug for the treatment of nephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha-globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff-man syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia or Wegener's granulomatosis.

17. The use according to claim 16, wherein the lupus is lupus erythematosus or systemic lupus erythematosus; and / or the pemphigus is pemphigus vulgaris.

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