Oxaazaspiro derivatives, preparation methods and medical applications thereof

Abstract

Disclosed are an oxazaspiro derivative, a preparation method thereof, and a pharmaceutical application thereof. Specifically, disclosed are an oxazaspiro derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a use thereof as a therapeutic agent, in particular, a use thereof as a PI3Kδ inhibitor and a use thereof in the preparation of a drug for treating a disease or condition improved by inhibiting PI3Kδ.

Description

Technical Field

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

[0002] Phosphoinositide 3-kinase (PI3K) is a key regulatory kinase in the PI3K / AKT / mTOR signaling pathway, and is 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 subtypes of PI3K, namely α, β, γ, and δ. Among them, PI3Kδ is mainly present in immune cells and blood cells, and is closely related to the occurrence of immunity, blood tumors, and inflammation (Cell, 170 (4), 605-635).

[0003] PI3Kδ is mainly expressed in immune cells and hematopoietic cells, and participates in the signal transduction of BCR in B cells, controlling the development and maturation of B cells in the body. When there is antigen stimulation of the body, the specific surface immunoglobulin Ig on the surface of BCR can bind to the antigen, resulting in the phosphorylation of ITAM in the intracellular segment of the CD79A / B complex. The phosphorylated ITAM can recruit and activate SYK, and further activate BTK and its downstream molecule PLCγ2. Activated SYK can bind to the P85 subunit of PI3Kδ, activate PI3Kδ, and promote the generation of PIP3. The generated PIP3 can recognize the N-terminal domain of BTK, and interact with it to mediate the recruitment of BTK to the membrane, thereby activating BTK-mediated B cell signal transduction and inducing the expression of many related genes. In addition, phosphorylated CD19 can also recruit PI3Kδ on the cell membrane, activate PI3Kδ, catalyze PIP2 to generate PIP3, activate AKT, and promote cell proliferation, migration, apoptosis and other processes (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 lymphoma, and the development of selective PI3Kδ inhibitors as drugs for the treatment of hematological tumors has received increasing attention.

[0004] Idelalisib is the first PI3Kδ selective inhibitor approved for marketing. It was approved in 2014 for the treatment of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Subsequently, in 2018, Duvelisib (acting on 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 blood tumors, since these early inhibitors usually have poor selectivity for PI3K kinases, many drug-related hepatotoxicity and gastrointestinal side effects have been seen in clinical practice. In order 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. The more representative ones are Parsaclisib, ME-401 and IOA-244, etc. These drugs are currently in different clinical stages.

[0005] IOA-244 is a second-generation PI3Kδ inhibitor developed by iOnctura (WO2011058149, WO2014121901). Compared with traditional PI3Kδ inhibitors, it is an ATP non-competitive inhibitor, which makes this drug highly selective for the inhibition of 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 major unmet medical need for the development of second-generation highly selective PI3Kδ inhibitors in relevant patient populations.

[0007] Currently, relevant 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 a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] R 0 , R 1 , R a , R b , R c , Rd , R e and R f are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a haloalkoxy group, a cyano group, a hydroxyl group, a hydroxyalkyl group, -(CH 2 ) 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 selected from halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) y NR g R h AND-OR 9 is substituted by one or more substituents; wherein R 0 , R 1 , R a , R b , R c , R d , R e and R f At least two of them, together with the carbon atom to which they are connected, form a spiro ring on the connected heterocycle, and the spiro ring is optionally substituted by one or more R';

[0012] R' is the same or different and is independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 and nitro;

[0013] R 5 is 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, -(CH 2 ) y NR g R h 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 、-NR 6 SO 2 R9 and substituted by one or more substituents in R;

[0014] The R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and the R is independently selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g R h 、-OR 9 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl;

[0015] R 2 and R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, cycloalkylalkyl, arylalkyl, heterocyclicalkyl and heteroarylalkyl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halogen, cyano, nitro, -(CH 2 ) y NR g R h 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 and-NR 6 SO 2 R 9 is substituted by one or more substituents;

[0016] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 、-OR i 、-COR i 、-COOR i 、-OS(O) x R i 、-S(O) x R i 、-NR 6 COR i 、-NR6 SO 2 R i , cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halogen, cyano, nitro, -(CH 2 ) y NR g R h 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 and-NR 6 SO 2 R 9 is substituted by one or more substituents;

[0017] or two adjacent R 3 Together with the carbon atom to which it is attached, it forms a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0018] R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl, wherein the alkyl, cycloalkyl and aryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] R 7 , R 8 , R g and R h 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;

[0020] or R 7 and R 8 , R g and R h 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;

[0021] R 9 and R i are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH 2 ) s NR 7 R 8 , cycloalkyl, heterocyclic group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group;

[0022] n is 1 or 2;

[0023] q is 0, 1, 2, 3, or 4;

[0024] s and y are the same or different and are each independently selected from 0, 1, 2, 3, 4 or 5; and

[0025] t and x are the same or different and are each independently selected from 0, 1 or 2.

[0026] The present disclosure also aims to provide a compound represented by general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0027]

[0028] in:

[0029] R a , R b , R c , R d , R e and R f are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a haloalkoxy group, a cyano group, a hydroxyl group, a hydroxyalkyl group, -(CH 2 ) 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 selected from halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) y NR g R h AND-OR 9 is substituted by one or more substituents;

[0030] R 0 , R 1 Together with the carbon atoms to which they are attached, they form a spiro ring on the attached heterocycle, which spiro ring is optionally substituted with one or more R';

[0031] R' is the same or different and is independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 and nitro;

[0032] R 5 is 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, -(CH 2 ) y NR g R h 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 、-NR 6 SO 2 R 9 and substituted by one or more substituents in R;

[0033] The R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and the R is independently selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g R h 、-OR 9 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl;

[0034] R 2 and R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, cycloalkylalkyl, arylalkyl, heterocyclicalkyl and heteroarylalkyl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halogen, cyano, nitro, -(CH2 ) y NR g R h 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 and-NR 6 SO 2 R 9 is substituted by one or more substituents;

[0035] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 、-OR i 、-COR i 、-COOR i 、-OS(O) x R i 、-S(O) x R i 、-NR 6 COR i 、-NR 6 SO 2 R i , cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halogen, cyano, nitro, -(CH 2 ) y NR g R h 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 and-NR 6 SO 2 R 9 is substituted by one or more substituents;

[0036] or two adjacent R 3Together with the carbon atom to which it is attached, it forms a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0037] R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl, wherein the alkyl, cycloalkyl and aryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0038] R 7 , R 8 , R g and R h 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;

[0039] or R 7 and R 8 , R g and R h 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;

[0040] R 9 and R i are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH 2 ) s NR 7 R 8 , cycloalkyl, heterocyclic group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group;

[0041] n is 1 or 2;

[0042] q is 0, 1, 2, 3, or 4;

[0043] s and y are the same or different and are each independently selected from 0, 1, 2, 3, 4 or 5; and

[0044] t and x are the same or different and are each independently selected from 0, 1 or 2.

[0045] 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, wherein R 0 and R 1 Together with the carbon to which it is attached, it forms a spiro ring on the attached heterocycle; preferably, it forms a spiro 3-6-membered ring; more preferably, it forms a spiro 3-6-membered carbocyclic ring; further preferably, it forms a spiro cyclopropyl.

[0046] 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:

[0047]

[0048] Where: m is 0, 1, 2 or 3;

[0049] R'、R a -R f , R 2 -R 5 and q are as defined in the general formula (I).

[0050] 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, wherein R 5 is an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are each independently selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g R h 、-OR 9 、-COR 9 、-COOR 9 、-OS(O) t R 9 、-S(O) t R 9 、-NR 6 COR 9 、-NR 6 SO 2 R 9 and substituted by one or more substituents in R;

[0051] The R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and the R is each independently selected from halogen, alkyl, haloalkyl and -OR 9 is substituted by one or more substituents;

[0052] R 6 , R 9 , R g , R h , y and t are as defined in the general formula (I) or (II).

[0053] 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, wherein R 5 is aryl or heteroaryl, wherein the aryl and heteroaryl are each independently optionally substituted by R, wherein R is selected from cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, and wherein R is each independently optionally substituted by one or more substituents selected from halogen, alkyl and haloalkyl;

[0054] 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;

[0055] More preferably, R 5 is a 6-10 membered aryl group, wherein the 6-10 membered aryl group is optionally replaced by a 3-8 membered heterocyclic group C 1-6 Alkyl substituted, the 3-8 membered heterocyclic group C 1-6 Alkyl is optionally selected from halogen, C 1-6 Alkyl and C 1-6 is substituted by one or more substituents in a haloalkyl group;

[0056] More preferably, R 5 is phenyl, said phenyl being substituted by morpholinylmethyl, and even more preferably, R 5 for

[0057] 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 (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0058]

[0059] in:

[0060] R 10 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) 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 -(CH 2 ) y NR g R h is substituted by one or more substituents;

[0061] R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, nitro, -(CH 2 ) y NR g R h , cycloalkyl, cycloalkyloxy, and cycloalkylalkyl;

[0062] Each R 12 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g R h 、-OR 9 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; when u is greater than or equal to 2, the two R 12 A spiro or bridged ring system can be formed on the morpholine ring;

[0063] w is 0, 1, 2, 3, or 4;

[0064] u is 0, 1, 2, 3, 4, 5, or 6;

[0065] R'、R a -R h , R 2 -R 4 , R 7 -R 9 , s, m, y and q are as defined in the general formula (I) or (II).

[0066] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R' is the same or different and each is independently selected from hydrogen atom, alkyl and halogen; preferably, R' is the same or different and each is independently selected from hydrogen atom, C 1-6 Alkyl and halogen; more preferably a hydrogen atom.

[0067] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl and cycloalkylalkyl, wherein the alkyl and cycloalkyl are each independently selected from alkyl, haloalkyl, halogen, cyano and -OR 9 is substituted by one or more substituents, R 9 As defined in general formula (I);

[0068] Preferably, R 2 and R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 More preferably, R 2 and R 4 All are hydrogen atoms.

[0069] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 AND-OR i , R 7 , R 8 , R i , s is as defined in the general formula (I);

[0070] Preferably, R 3 are the same or different and are each independently selected from hydrogen, halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl;

[0071] More preferably, R 3 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; more preferably fluorine.

[0072] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen atom, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each independently substituted by one or more substituents selected from alkyl, alkoxy, halogen, hydroxyl and hydroxyalkyl; preferably, R 6 A hydrogen atom or C 1-6 alkyl.

[0073] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt 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;

[0074] Preferably, R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a 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 alkylene group is substituted by one or more substituents of alkoxy and halogen.

[0075] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 9 and R iare 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; wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen group, an alkyl group, an alkoxy group, a haloalkyl group, a cyano group and an amino group;

[0076] Preferably, R 9 and R i are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a cycloalkyl group; wherein the alkyl group and the cycloalkyl group are each independently optionally substituted by one or more substituents selected from a halogen group, an alkyl group, an alkoxy group and a haloalkyl group;

[0077] More preferably, R 9 and R i are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0078] In some preferred embodiments of the present disclosure, a compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 10 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 AND-OR 9 , R 7 , R 8 , R 9 and s are as defined in formula (III);

[0079] Preferably, R 10 are the same or different and are each independently a hydrogen atom, a halogen and a C 1-6 An alkyl group; more preferably a hydrogen atom.

[0080] In some preferred embodiments of the present disclosure, a compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cyano and -(CH 2 ) y NR g R h , R g , R hand y are as defined in formula (III);

[0081] Preferably, R 11 are the same or different and are each independently a hydrogen atom, a halogen and a C 1-6 An alkyl group; more preferably a hydrogen atom.

[0082] In some preferred embodiments of the present disclosure, a compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 12 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) y NR g R h AND-OR 9 , R 9 , R g , R h and y are as defined in formula (III);

[0083] Preferably, R 12 are the same or different and are each independently a hydrogen atom, a halogen and a C 1-6 An alkyl group; more preferably a hydrogen atom.

[0084] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R a -R f are the same or different and are each independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl and hydroxyalkyl;

[0085] Preferably, R a -R f are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; More preferably, R a -R f All are hydrogen atoms.

[0086] In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0087] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) 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.

[0088] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein s and y are the same or different and are each independently selected from 0 or 1, preferably 0.

[0089] In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t and x are the same or different and are each independently selected from 0 or 2, preferably 2.

[0090] In some preferred embodiments of the present disclosure, a compound represented by the general formula (II) or (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2, preferably 0 or 1, and more preferably 0.

[0091] In some preferred embodiments of the present disclosure, a compound represented by the general formula (III) 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 or 1, and more preferably 0.

[0092] In some preferred embodiments of the present disclosure, a compound represented by the general formula (III) 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 or 1, and more preferably 0.

[0093] In some preferred embodiments of the present disclosure, a compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, wherein R', R 10 , R 12 , R a , R b , R c , R d , R e and R f are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6Alkyl; m is 0 or 1; w is 0 or 1; u is 0 or 1; R 11 , R 2 and R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 3 are the same or different and are each independently selected from hydrogen, halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl; and q is 1.

[0094] Table A Typical compounds of the present disclosure include, but are not limited to:

[0095]

[0096]

[0097]

[0098] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0099]

[0100] The compound of the general formula (IA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is reacted with the compound of the general formula (IB) or its pharmaceutically acceptable salt to obtain the compound of the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0101] Where R 0 -R 5 , R a -R f , n and q are as defined in the general formula (I).

[0102] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0103]

[0104] The compound of the general formula (IA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is reacted with the compound of the general formula (IIB) or its pharmaceutically acceptable salt to obtain the compound of the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0105] Among them, R', R 2 -R 5 , R a -R f , m and q are as defined in the general formula (II).

[0106] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0107]

[0108] The compound of general formula (IIIA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt is reacted with the compound of general formula (IIB) or its pharmaceutically acceptable salt to obtain the compound of general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0109] Among them, R', R 2 -R 4 , R a -R f , R 10 -R 12 , q, u, w and m are as defined in the general formula (III).

[0110] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure represented by general formula (I), (II), (III) or 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.

[0111] The present disclosure further relates to the use of a compound represented by the general formula (I), (II), (III) or Table A, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a drug for inhibiting PI3Kδ.

[0112] The present disclosure further relates to the use of the compounds of general formula (I), (II), (III) or shown in Table A or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases;The cancer is 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 tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma (the above tumors are all corresponding malignant tumors), and the leukemia is preferably selected from chronic lymphocytic leukemia. The present invention relates to a method for treating a leukemia of at least one embodiment of the present invention, wherein the present invention is preferably selected from the group consisting of 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), and the autoimmune disease is preferably selected from the group consisting of asthma, rheumatoid arthritis, acute disseminated encephalomyelitis, and the like. (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 hemorrhage-nephritis 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, sicca syndrome, 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. ;

[0113] The present disclosure also relates to a method for inhibiting PI3Kδ, comprising administering to a patient in need thereof an effective inhibitory amount of a compound of formula (I), (II), (III) or Table A or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0114] The present disclosure also relates to a method for treating and / or preventing a PI3Kδ-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III) or shown in Table A or its tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0115] The present disclosure also relates to a method for treating and / or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases, comprising administering to a patient in need thereof an effective amount of a compound of formula (I), (II), (III) or shown in Table A or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same;The cancer is 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 tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, and the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia, The present invention relates to 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, myeloma and other autoimmune diseases. 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 diseases, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, sicca syndrome, 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. ;

[0116] The present disclosure further relates to a compound represented by general formula (I), (II), (III) or Table A or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used as a drug.

[0117] The present disclosure also relates to compounds represented by general formula (I), (II), (III) or Table A, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are used as PI3Kδ inhibitors.

[0118] The present disclosure also relates to a compound represented by the general formula (I), (II), (III) or 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 in treating and / or preventing PI3Kδ-mediated diseases.

[0119] The present disclosure also relates to compounds of general formula (I), (II), (III) or shown in Table A or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are used for treating and / or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases;The cancer is 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 tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, and the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia, The present invention relates to 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, myeloma and other autoimmune diseases. 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 diseases, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, sicca syndrome, 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. ;

[0120] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0121] As a general guide, the active compounds of the present disclosure are preferably in a unit dosage form, or in a form that a patient can self-administer in a single dose. The unit dosage form of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit dosages can be 0.1 to 1000 mg.

[0122] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are 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.

[0123] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by 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.

[0124] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0125] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants 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.

[0126] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a 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 an antioxidant.

[0127] 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, or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0128] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0129] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0130] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0131] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of 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.

[0132] 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 factors: 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.

[0133] Terminology

[0134] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0135] 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 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 and 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 having 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 D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0136] 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, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-、1,1-propylene(-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available attachment point, and the substituents are preferably independently and optionally selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0137] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0138] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0139] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, 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, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.

[0140] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 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 / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0141]

[0142] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, 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). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, 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 condensed cycloalkyl include:

[0143]

[0144] 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, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0145]

[0146] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) 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

[0147] 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, heteroaryl.

[0148] 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 can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0149] 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, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms being 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 to 4 (e.g. 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (e.g. 1, 2 and 3); more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0150] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 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 / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0151]

[0152] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system. The polycyclic heterocyclic group, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and 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 yuan, 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 a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a 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 radical. Non-limiting examples of fused heterocyclic radicals include:

[0153]

[0154] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing 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, 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:

[0155]

[0156] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0157] wait.

[0158] 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, heteroaryl.

[0159] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with 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 connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0160]

[0161] 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 hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0162] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. 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, and non-limiting examples thereof include:

[0163]

[0164] 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, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0165] 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".

[0166] The term "amino protecting group" is to protect the amino group with a group that is easily removed in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.

[0167] The term "hydroxy protecting group" refers to a group known in the art as being suitable for protecting a hydroxy group, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the hydroxyl protecting group. As an example, preferably, the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 Alkoxy substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy substituted C 1-4 Alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aromatic) acyl, for example: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 Aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10 aryloxy)carbonyl.

[0168] The term "arylalkyl" refers to an aryl-alkylene- group in which aryl and alkylene are as defined above.

[0169] The term "heteroarylalkyl" refers to a heteroaryl-alkylene- group in which heteroaryl and alkylene are as defined above.

[0170] The term "cycloalkylalkyl" refers to a cycloalkyl-alkylene- group in which cycloalkyl and alkylene are as defined above.

[0171] The term "heterocyclylalkyl" refers to a heterocyclyl-alkylene- group in which the heterocyclyl and alkylene groups are as defined above.

[0172] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0173] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0174] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0175] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0176] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0177] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0178] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0179] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0180] The term "hydroxy" refers to -OH.

[0181] The term "thiol" refers to -SH.

[0182] The term "amino" refers to -NH 2 .

[0183] The term "cyano" refers to -CN.

[0184] The term "nitro" refers to -NO 2 .

[0185] The term "oxo" refers to "=0".

[0186] The term "carbonyl" refers to C=O.

[0187] The term "carboxy" refers to -C(O)OH.

[0188] 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.

[0189] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and Two configurations.

[0190] 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 a 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 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for disease, or as tracers for pharmacodynamic, pharmacokinetics or receptor studies.

[0191] The present disclosure also includes various deuterated forms of compounds of formula (I), (II), (III) or Table A. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I), (II), (III) or Table A with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds of formula (I), (II), (III) or Table A, or they can be synthesized using deuterated reagents using conventional techniques, including but not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0192] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and 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.

[0193] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0194] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and 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, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0195] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or 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.

[0196] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0197] The term "pharmaceutically acceptable" as used herein refers to those 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.

[0198] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0199] 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 only for illustrative purposes and not for limitation.

[0200] Synthesis method of the disclosed compound

[0201] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0202] Solution 1

[0203] The method for preparing the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt disclosed herein comprises the following steps:

[0204]

[0205] The compound of the general formula (IA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt is reacted with the compound of the general formula (IB) or its pharmaceutically acceptable salt (preferably hydrochloride) 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,

[0206] Where R 0 -R 5 , R a -R f , n and q are as defined in the general formula (I).

[0207] Solution 2

[0208] The present invention discloses a method for preparing a compound represented by general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0209]

[0210] The compound of general formula (IA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt is reacted with the compound of general formula (IIB) or its pharmaceutically acceptable salt (preferably hydrochloride) 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,

[0211] Among them, R', R2 -R 5 , R a -R f , m and q are as defined in the general formula (II).

[0212] Option 3

[0213] The present invention discloses a method for preparing a compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0214]

[0215] The compound of general formula (IIIA) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt is reacted with the compound of general formula (IIB) or its pharmaceutically acceptable salt (preferably hydrochloride) under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound of general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt,

[0216] Among them, R', R 2 -R 4 , R a -R f , R 10 -R 12 , q, u, w and m are as defined in the general formula (III).

[0217] The reagents providing alkaline conditions for the above reaction include organic bases and inorganic bases, wherein the organic bases include but are not limited to triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, and 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 and / or 4-dimethylaminopyridine; more preferably a combination of N,N-diisopropylethylamine and 4-dimethylaminopyridine.

[0218] 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)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, also known as N,N,N',N'-tetramethyl-O-(7-azabenzotriazole) -1-yl) urea hexafluorophosphate, O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and / or 1-hydroxybenzotriazole, or HATU alone; more preferably a combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole.

[0219] 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

[0220] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0221] Example

[0222] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0223] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMOUltimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0224] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0225] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0226] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0227] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0228] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0229] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0230] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0231] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0232] 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.

[0233] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0234] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0235] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0236] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0237] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0238] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0239] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0240] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0241] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound and the developing solvent system of the thin layer chromatography include: A: dichloromethane / methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0242] Example 1

[0243] (6-Fluoro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 1

[0244]

[0245] first step

[0246] tert-Butyl 1-(4-(Morpholinylmethyl)phenyl)hydrazine-1-carboxylate 2b

[0247] Under argon atmosphere, compound 4-(4-iodobenzyl)morpholine 2a (51 g, 168.24 mmol, prepared by the method disclosed in Example 17.1 on page 59 of the specification of patent application "WO200832191A2") and tert-butyl carbazate (23.347 g, 176.66 mmol, Shaoyuan) were dissolved in 400 mL of dimethyl sulfoxide, stirred for 10 minutes, and then copper iodide (1.603 g, 8.42 mmol) was added, the temperature was raised to 50°C, and the reaction was stirred for 17 hours. 400 mL of water was added, the aqueous phase was extracted with ethyl acetate (300 mL×6), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 2b (51 g, yield 98.6%).

[0248] MS m / z(ESI):308.1[M+1].

[0249] Step 2

[0250] 4-(4-Hydrazinobenzyl)morpholine 2c hydrochloride

[0251] At 0°C, compound 2b (51 g, 165.91 mmol) was dissolved in 80 mL of methanol, and a solution of hydrogen chloride in 1,4-dioxane (350 mL, 4.0 M, Yanfeng Technology) was added dropwise, and the mixture was naturally heated to room temperature and stirred for 17 hours. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of the crude title compound 2c (45.4 g), which was used directly in the next step without purification.

[0252] Step 3

[0253] 3-((2-Fluorophenyl)thio)propanoic acid 1e

[0254] 2-Fluorothiophenol 1d (50 g, 390.11 mmol, Shaoyuan) and potassium carbonate (70 g, 507.14 mmol, Guoyao) were dissolved in N,N-dimethylformamide (500 mL), stirred at 60°C for 1 hour, and 3-bromopropionic acid (65.6 g, 429.15 mmol, Shaoyuan) was added, and the reaction was continued at 60°C for 3 hours. After the reaction was completed, 1000 mL of water was added to the reaction solution, and ethyl acetate was extracted (300 mL x 2). The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid, and ethyl acetate was extracted (400 mL x 3). The organic phases were combined, washed with water (400 mL x 3) and saturated saline solution (400 mL x 2) in turn, dried over anhydrous sodium sulfate for 15 minutes, filtered, and concentrated under reduced pressure to obtain the crude title compound 1e (70 g), which was directly used in the next step without purification.

[0255] MS m / z(ESI):198.9[M-1].

[0256] Step 4

[0257] 8-Fluorothiochroman-4-one 1f

[0258] Compound 1e (70 g, 356.65 mmol) was dissolved in concentrated sulfuric acid (200 mL) and stirred at 0°C for 3 hours. After the reaction was completed, the reaction solution was poured into 1000 mL of ice water and extracted with ethyl acetate (400 mL x 3). The organic phases were combined, washed with saturated saline solution (400 mL x 2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1f (30 g), which was used directly in the next step without purification.

[0259] Step 5

[0260] 2-(8-Fluoro-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 1g

[0261] Sodium ethoxide (52 g, 152.59 mmol, 20% w / w ethanol solution, Adamas) was added to a 500 mL three-necked flask, and diethyl oxalate (16.7 g, 114.47 mmol, dissolved in 100 mL toluene, Shaoyuan) was slowly added dropwise at 0°C, followed by slowly adding compound 1f (13.9 g, 76.28 mmol, dissolved in 100 mL toluene). The reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, and it was extracted with dichloromethane (200 mL x 2), the aqueous phase was adjusted to pH about 2 with 5M HCl solution, and extracted with ethyl acetate (250 mL x 3), the organic phases were combined, washed with saturated saline solution (200 mL x 2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1g (22 g), which was directly used in the next step without purification.

[0262] MS m / z(ESI):280.9[M-1].

[0263] Step 6

[0264] 2-(8-Fluoro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 1h

[0265] Compound 1g (22g, 77.93mmol) was dissolved in 250mL of dichloromethane, and m-chloroperbenzoic acid (34.8g, 171.46mmol, Wokai) was added in batches under ice-bath cooling, and stirred at room temperature for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 1h (24.5g, yield 100%).

[0266] MS m / z(ESI):313.0[M-1].

[0267] Step 7

[0268] Ethyl 6-fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide 1i

[0269] Compound 1h (9.4 g, 29.90 mmol), the hydrochloride of compound 2c (6.8 g, 75%) and glacial acetic acid (3.6 g, 59.94 mmol, Shanghai test) were dissolved in 200 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×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 1i (7.5 g, yield 51.6%).

[0270] MS m / z(ESI):486.1[M+1].

[0271] Step 8

[0272] 6-Fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 1a

[0273] Compound 1i (14 g, 29.07 mmol) was dissolved in 150 mL of tetrahydrofuran, and sodium hydroxide aqueous solution (58.2 mL, 2 M) was added, and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust the pH to about 3, and the mixture was concentrated under reduced pressure to obtain the crude title compound 1a (21.2 g), which was used directly in the next step without purification.

[0274] MS m / z(ESI):458.0[M+1].

[0275] Step 9

[0276] (6-Fluoro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 1

[0277] Compound 1a (100 mg, 218.59 mmol) and 4-oxa-7-azaspiro[2.5]octane hydrochloride (33 mg, 220.77 mmol, Jiangsu Aikon), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 651.77 mmol), 1-hydroxybenzotriazole (99 mg, 655.77 mmol), N,N-diisopropylethylamine (110 mg, 1.09 mmol), and 4-dimethylaminopyridine (53 mg, 437.18 mmol) were dissolved in dichloromethane (30 mL) and stirred at room temperature for 16 hours. 50 mL of water was added, and a mixed solvent (60 mL) of dichloromethane and methanol (v:v=10:1) was used for extraction. The organic phases were combined, washed with water (60 mL) and saturated saline solution (60 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to give the title product 1 (60 mg, yield: 49.6%).

[0278] MS m / z(ESI):553.3[M+1].

[0279] 1 H NMR (500 MHz, DMSO-d 6 ): δ7.62-7.44(m,6H),6.66(d,1H),4.99(d,2H),4.07(t,1H),3.90(s,1H),3.76-3.59(m,9H),3.32(s,1H),2.42(s,4H),0.73-0.60(m,4H).

[0280] Example 2

[0281] (6-Chloro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 2

[0282]

[0283] first step

[0284] tert-Butyl 1-(4-(Morpholinylmethyl)phenyl)hydrazine-1-carboxylate 2b

[0285] Under argon atmosphere, compound 4-(4-iodobenzyl)morpholine 2a (51 g, 168.24 mmol, prepared by the method disclosed in Example 17.1 on page 59 of the specification of patent application "WO200832191A2") and tert-butyl carbazate (23.347 g, 176.66 mmol, Shaoyuan) were dissolved in 400 mL of dimethyl sulfoxide, stirred for 10 minutes, and then copper iodide (1.603 g, 8.42 mmol) was added, the temperature was raised to 50°C, and the reaction was stirred for 17 hours. 400 mL of water was added, the aqueous phase was extracted with ethyl acetate (300 mL×6), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 2b (51 g, yield 98.6%).

[0286] MS m / z(ESI):308.1[M+1].

[0287] Step 2

[0288] 4-(4-Hydrazinobenzyl)morpholine 2c hydrochloride

[0289] At 0°C, compound 2b (51 g, 165.91 mmol) was dissolved in 80 mL of methanol, and a solution of hydrogen chloride in 1,4-dioxane (350 mL, 4.0 M, Yanfeng Technology) was added dropwise, and the mixture was naturally heated to room temperature and stirred for 17 hours. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of the crude title compound 2c (45.4 g), which was used directly in the next step without purification.

[0290] Step 3

[0291] 2-(8-Chloro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 2e

[0292] Compound 2-(8-chloro-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 2d (25.7 g, 86.03 mmol, prepared by the method disclosed in the intermediate E4 on page 169 of the specification of patent "CN102695710B") was dissolved in 250 mL of dichloromethane, and m-chloroperbenzoic acid (43.664 g, 215.07 mmol) was added in batches under ice-bath cooling, and stirred at room temperature for 17 hours. Filter, concentrate the filtrate under reduced pressure, and purify the residue with CombiFlash rapid preparation instrument using eluent system A to obtain the title compound 2e (28.323 g, yield 99.5%).

[0293] MS m / z(ESI):330.9[M+1].

[0294] Step 4

[0295] 6-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 2f

[0296] Compound 2e (10 g, 30.24 mmol), the hydrochloride of compound 2c (9.192 g, 75%) and glacial acetic acid (3.632 g, 60.48 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×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 2f (10 g, yield 65.9%).

[0297] MS m / z(ESI):502.0[M+1].

[0298] Step 5

[0299] 6-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 2g

[0300] Compound 2f (10 g, 19.92 mmol) was dissolved in 150 mL of tetrahydrofuran, and sodium hydroxide aqueous solution (39.8 mL, 2.5 M) was added, and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust the pH to about 3, and the mixture was concentrated under reduced pressure to obtain a crude title compound 2g (17.028 g), which was used directly in the next step without purification.

[0301] MS m / z(ESI):474.0[M+1].

[0302] Step 6

[0303] (6-Chloro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 2

[0304] Compound 2g (544 mg, 633.61 μmol, 55.2%), 4-oxa-7-azaspiro[2.5]octane hydrochloride (97 mg, 648.32 μmol, Yao Shi), HATU (290 mg, 762.70 μmol) and N,N-diisopropylethylamine (411 mg, 3.18 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, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title product 2 (108 mg, yield: 30.0%).

[0305] MS m / z(ESI):569.0[M+1].

[0306] 1 H NMR (500 MHz, DMSO-d 6 ): δ7.66-7.64(m,1H),7.54-7.40(m,5H),6.83-6.81(m,1H),5.02-5.00(m,2H),4. 08(s,1H),3.92(s,1H),3.75-3.58(m,10H),2.46-2.41(m,4H),0.73-0.61(m,4H).

[0307] Example 3

[0308] (9-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 3

[0309]

[0310] first step

[0311] 5-Methoxythiochroman-4-one 3b

[0312] 3-(3-Methoxyphenylthio)formic acid 3a (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-mouth bottle and stirred at room temperature for 3 hours. The reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product 3b (300 mg, yield: 2.73%).

[0313] Step 2

[0314] 2-(5-Methoxy-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 3c

[0315] Sodium ethoxide (1.44 g, 4.23 mmol, 20% w / w ethanol solution) was dissolved in 20 mL toluene, cooled to 0°C, and a 20 mL toluene solution of diethyl oxalate (463 mg, 3.166 mmol) was added dropwise, and then compound 3b (410 mg, 2.11 mmol) was added, and the mixture was reacted at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, 100 mL of water was added to the residue, and dichloromethane was extracted (50 mL). The aqueous phase was adjusted to pH 2 with 5M hydrochloric acid solution, and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (20 mL×2), and the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3c (900 mg). The product was directly used for the next step without purification.

[0316] Step 3

[0317] 2-(5-methoxy-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 3d

[0318] The crude product 3c (900 mg, 3.058 mmol) was dissolved in 30 mL of dichloromethane, 3-chloroperoxybenzoic acid (1.2 g, 6.95 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title compound 3d (550 mg, yield: 55.1%).

[0319] Step 4

[0320] 9-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 3e

[0321] Compound 3d (550 mg, 1.68 mmol) was dissolved in 30 mL of ethanol, and the hydrochloride of compound 2c (384 mg) and glacial acetic acid (203 mg, 3.3804 mmol) were added, and 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 was dried to obtain the title product 3e (700 mg), with a yield of 83.4%.

[0322] Step 5

[0323] 9-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 3f

[0324] Compound 3e (10.2 g, 20.5 mmol) was dissolved in 50 mL of tetrahydrofuran, and sodium hydroxide aqueous solution (3 M, 2.8 mL) was added, and stirred at room temperature for 4 hours. The reaction solution was adjusted to pH about 2 with 5.0 M hydrochloric acid solution, and concentrated under reduced pressure to obtain a crude title product 3f (1 g, 60% purity), which was directly used in the next step without purification.

[0325] Step 6

[0326] (9-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 3

[0327] The crude compound 3f (300 mg, 332.26 μmol, purity 60%), 4-oxa-7-azaspiro[2.5]octane hydrochloride (50 mg, 334.18 μmol, Yao Shi), HATU (152 mg, 399.76 μmol) and N,N-diisopropylethylamine (215 mg, 1.66 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, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title product 3 (40 mg, yield: 21.3%).

[0328] MS m / z(ESI):565.0[M+1].

[0329] 1 H NMR (500 MHz, CDCl 3 )δ7.77-7.75(m,1H),7.59-7.56(m,1H),7.42-7.39(m,2H),7.35-7.33( m,1H),7.31-7.30(m,1H),7.03-7.01(m,1H),4.73-4.71(m,2H),4.33-4. 32(m,1H),4.19(s,1H),3.89-3.82(m,3H),3.79-3.74(m,5H),3.57(s,2H ),3.13(s,3H),2.50-2.48(m,4H),0.87-0.85(m,2H),0.74-0.72(m,2H).

[0330] Example 4

[0331] (7-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone

[0332]

[0333]

[0334] first step

[0335] 2-(7-Methoxy-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl 4b

[0336] Sodium ethoxide (19.267 g, 56.62 mmol, 20% w / w ethanol solution) 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, extracted with dichloromethane (200 mL×2), the aqueous phase was adjusted to pH about 2 with 5 M hydrochloric acid solution, extracted with ethyl acetate (200 mL×3), the combined organic phases were washed with saturated brine (200 mL×2), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 4b (8.3 g), which was directly used for the next step without purification.

[0337] Step 2

[0338] 2-(7-Methoxy-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl 4c

[0339] The crude 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 in batches under ice-bath cooling, and stirred at room temperature for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title compound 4c (8.8 g, yield: 95.6%).

[0340] Step 3

[0341] 7-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 4d

[0342] Compound 4c (8.8 g, 26.96 mmol) was dissolved in 200 mL of ethanol, and the hydrochloride of 2c (6.7 g) and glacial acetic acid (3.239 g, 53.93 mmol) were added, and 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 was dried to obtain the title product 4d (10.2 g), with a yield of 76.0%.

[0343] Step 4

[0344] 7-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 4e

[0345] Compound 4d (10.2 g, 20.5 mmol) was dissolved in 100 mL of tetrahydrofuran, and sodium hydroxide aqueous solution (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, purity 8.8%).

[0346] Step 5

[0347] (7-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone

[0348] Compound 4e (300 mg, 332.26 μmol, 58.8%), 4-oxa-7-azaspiro[2.5]octane hydrochloride (50 mg, 334.18 μmol, Yao Shi), HATU (151 mg, 397.13 μmol) and N,N-diisopropylethylamine (215 mg, 1.66 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 17 hours. 10 mL of saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title product 4 (47 mg, yield: 25.1%).

[0349] MS m / z(ESI):565.1[M+1].

[0350] 1 H NMR (500 MHz, CDCl 3)δ7.62-7.60(m,1H),7.53-7.49(m,2H),7.46-7.40(m,2H),7.07-6.89(m,1H),6.83-6.81(m,1H),4.76-4.75(m,2H),4.31-4.29(m,1H) ,4.18-4.16(m,1H),3.91-3.88(m,5H),3.83-3.78(m,6H),3.63-3.60(m,2H),2.54-2.51(m,4H),0.87-0.84(m,2H),0.72-0.68(m,2H).

[0351] Example 5

[0352] (6-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 5

[0353]

[0354] first step

[0355] 3-((2-Methoxyphenyl)thio)propanoic acid 5b

[0356] 2-Methoxythiophenol 5a (25.0 g, 178.31 mmol, Shaoyuan) and potassium carbonate (36.9 g, 267.50 mmol, Guoyao) were dissolved in 200 mL N,N-dimethylformamide, stirred at 60°C for 30 minutes under nitrogen atmosphere, cooled to room temperature, and 3-bromopropionic acid (28.6 g, 187.28 mmol, Admas) was added, and continued to stir at 60°C for 3 hours under nitrogen atmosphere. 1000 mL of water was added to the reaction solution, and ethyl acetate was extracted (300 mL×2). The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid, and ethyl acetate was extracted (400 mL×2). The combined organic phases were washed with water (400 mL×2) and saturated brine (400 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 5b (37 g), with a yield of 98%.

[0357] MS m / z(ESI):213.1[M-1].

[0358] Step 2

[0359] 8-Methoxythiochroman-4-one 5c

[0360] Compound 5b (37 g, 174.3 mmol) was dissolved in concentrated sulfuric acid (200 mL) and stirred at 0°C for 2 hours. The reaction solution was poured into 1000 mL of ice water, extracted with ethyl acetate (300 mL x 3), the organic phase was washed with saturated brine (300 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 5c (1.74 g, yield: 4.3%).

[0361] MS m / z(ESI):194.9[M+1].

[0362] Step 3

[0363] 2-(8-Methoxy-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 5d

[0364] Sodium ethoxide (6.10 g, 17.92 mmol, 20% w / w ethanol solution) was added to a 100 mL three-necked flask, diethyl oxalate (1.97 g, 13.49 mmol, dissolved in 30 mL toluene) and compound 5c (1.74 g, 8.95 mmol, dissolved in 30 mL toluene) were added at 0°C, and the mixture was reacted 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×2). The aqueous phase was adjusted to a pH of about 2 with a 5M hydrochloric acid solution, and extracted with ethyl acetate (70 mL×3). The organic phases were combined, washed with saturated brine (60 mL×2), and dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 5d (2.6 g) with a yield of 98.6%.

[0365] MS m / z(ESI):295.0[M+1].

[0366] Step 4

[0367] 2-(8-Methoxy-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 5e

[0368] Compound 5d (2.6 g, 8.83 mmol) was dissolved in 250 mL of dichloromethane, and m-chloroperbenzoic acid (3.9 g, 19.47 mmol) was added in portions under ice-bath cooling, and stirred at room temperature for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 5e (2.8 g, yield 97.1%).

[0369] MS m / z(ESI):326.9[M+1].

[0370] Step 5

[0371] 6-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 5f

[0372] Compound 5e (1.3 g, 3.98 mmol), the hydrochloride of compound 2c (825.7 mg) and glacial acetic acid (478.4 mg, 7.96 mmol) 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×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 5f (1.63 g, yield 82.2%).

[0373] MS m / z(ESI):498.0[M+1].

[0374] Step 6

[0375] 6-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 5g

[0376] Compound 5f (1.63 g, 3.27 mmol) was dissolved in 30 mL of tetrahydrofuran, and sodium hydroxide aqueous solution (6.5 mL, 2.5 M) was added and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust the pH to about 3, and the mixture was concentrated under reduced pressure to obtain a crude title compound 5g (2.4 g, yield 156.0%), which was used directly in the next step without purification.

[0377] MS m / z(ESI):470.0[M+1].

[0378] Step 7

[0379] (6-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 5

[0380] The crude compound 5g (330mg, 421.71μmol, 60% purity), 4-oxa-7-azaspiro[2.5]octane hydrochloride (63mg, 421.74μmol, Jiangsu Aikang) and HATU (297.6mg, 1.26mmol) were dissolved in 30mL N,N-dimethylformamide, and N,N-diisopropylethylamine (326mg, 2.53mmol) was added and stirred for 2 hours. 60mL of water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (80mL×3), the organic phases were combined, washed with saturated saline solution (80mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 5 (102mg, yield 42.8%).

[0381] MS m / z(ESI):565.1[M+1].

[0382] 1 H NMR (500 MHz, DMSO-d 6 ): δ7.53-7.50(m,2H),7.45-7.37(m,3H),7.25(d,1H),6.39-6.37(m,1H),4.80(d,2H),4 .07(m,2H),3.91(s,3H),3.74-3.57(m,9H),3.32(s,1H),2.41(t,4H),0.74-0.59(m,4H).

[0383] Example 6

[0384] (6-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 6

[0385]

[0386]

[0387] first step

[0388] 3-(o-Tolylthio)propionic acid 6b

[0389] 2-Methylthiophenol 6a (25.0 g, 201.2 mmol, Shaoyuan) and potassium carbonate (41.7 g, 301.9 mmol) were dissolved in 200 mL N,N-dimethylformamide and stirred at 60 ° C for 30 minutes under nitrogen atmosphere. After cooling to room temperature, 3-bromopropionic acid (32.3 g, 211.4 mmol, Admas) was added and continued to stir at 60 ° C for 3 hours under nitrogen atmosphere. 1000 mL of water was added to the reaction solution, and ethyl acetate was extracted (300 mL × 2). The aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid, and ethyl acetate was extracted (400 mL × 2). The combined organic phases were washed with water (400 mL × 2) and saturated brine (400 mL × 2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 6b (39 g), with a yield of 98%.

[0390] MS m / z(ESI):195.2[M-1].

[0391] Step 2

[0392] 8-Methylthiochroman-4-one 6c

[0393] Compound 6b (39 g, 198.6 mmol) was dissolved in concentrated sulfuric acid (200 mL) and stirred at 0°C for 2 hours. The reaction solution was poured into 1000 mL of ice water, extracted with ethyl acetate (300 mL x 3), the organic phase was washed with saturated brine (300 mL x 2), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 6c (15.5 g, yield: 43%).

[0394] MS m / z(ESI):178.9[M+1].

[0395] Step 3

[0396] 2-(8-Methyl-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 6d

[0397] Sodium ethoxide (59 g, 173.93 mmol, 20% w / w ethanol solution) was added to a 500 mL three-necked flask, diethyl oxalate (19 g, 130.49 mmol, dissolved in 100 mL toluene) and compound 6c (15.5 g, 86.9 mmol, dissolved in 100 mL toluene) were added at 0°C, and the mixture was reacted 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×2). The aqueous phase was adjusted to a pH of about 2 with a 5M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine (200 mL×2), and dried over anhydrous sodium sulfate for 15 min, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 6d (24 g), with a yield of 99.0%.

[0398] MS m / z(ESI):279.0[M+1].

[0399] Step 4

[0400] 2-(8-Methyl-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 6e

[0401] Compound 6d (24 g, 86.23 mmol) was dissolved in 250 mL of dichloromethane, and m-chloroperbenzoic acid (29 g, 172.5 mmol) was added in batches under ice-bath cooling, and stirred at room temperature for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 6e (26 g, yield 97.1%).

[0402] MS m / z(ESI):310.9[M+1].

[0403] Step 5

[0404] 6-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 6f

[0405] Compound 6e (15 g, 49.01 mmol), the hydrochloride of compound 2c (10 g) and glacial acetic acid (5.9 g, 98.11 mmol) 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×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 6f (20 g, yield 86.9%).

[0406] MS m / z(ESI):482.0[M+1].

[0407] Step 6

[0408] 6-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 6g

[0409] Compound 6f (14 g, 29.07 mmol) was dissolved in 150 mL of tetrahydrofuran, and sodium hydroxide aqueous solution (58.2 mL, 2.5 M) was added, and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust the pH to about 3, and the mixture was concentrated under reduced pressure to obtain a crude title compound 6g (21.2 g), which was used directly in the next step without purification.

[0410] MS m / z(ESI):454.0[M+1].

[0411] Step 7

[0412] (6-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 6

[0413] Compound 6g (250 mg, 330.75 μmol), 4-oxa-7-azaspiro[2.5]octane hydrochloride (49.5 mg, 330.77 μmol) and HATU (233.4 mg, 992.28 μmol) were dissolved in 30 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (256 mg, 1.98 mmol) was added, and the mixture was stirred for 2 hours. 60 mL of water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (80 mL×3), the organic phases were combined, washed with saturated saline solution (80 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 6 (40 mg, yield 22%).

[0414] MS m / z(ESI):549.1[M+1].

[0415] 1 H NMR (500 MHz, DMSO-d 6 ): δ7.52-7.49(m,2H),7.42-7.35(m,4H),6.71-6.68(m,1H),4.89(d,2H),4.09(t,2H),3.92(s,3H),3.74-3.57(m,9H),3.29(s,1H),2.41(t, 4H),0.72-0.61(m,4H).

[0416] Example 7

[0417] (7-Chloro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 7

[0418]

[0419] first step

[0420] 2-(7-Chloro-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 7b

[0421] Sodium ethoxide (62.0 g, 182.2 mmol, 20% w / w ethanol solution) was added to a 500 mL single-mouth bottle, and 300 mL of a toluene solution of diethyl oxalate (19.9 g, 136.2 mmol) was added at 0°C, and then 7-chlorothiochromane-4-one 7a (18.0 g, 90.6 mmol, prepared by the method disclosed in "Organic Letters, 2020, 22 (3), 1155-1159") was added, and stirred at room temperature for 17 h. The reaction solution was concentrated under reduced pressure, 400 mL of water was added to the residue, and dichloromethane was extracted (200 mL × 2). The aqueous phase was adjusted to a pH of about 2 with a 5M hydrochloric acid solution, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (200 mL × 2), and the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 7b (13.7 g). The product was directly subjected to the next step without purification.

[0422] Step 2

[0423] 2-(7-Chloro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 7c

[0424] The crude compound 7b (11.80 g, 36.15 mmol) was dissolved in 150 mL of dichloromethane, 3-chloroperoxybenzoic acid (17.2 g, 81.79 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title compound 7c (12.3 g) with a yield of 98.3%.

[0425] Step 3

[0426] 7-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 7d

[0427] Compound 7c (11.3 g, 33.6 mmol) was dissolved in 80 mL of ethanol, and the hydrochloride of compound 2c (9.0 g) and glacial acetic acid (20 mL) were added, and 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 was dried under vacuum to obtain the title product 7d (13.9 g), with a yield of 83.2%.

[0428] Step 4

[0429] 7-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 7e

[0430] Compound 7d (13.9 g, 28.3 mmol) was dissolved in 100 mL of tetrahydrofuran, and an aqueous solution of sodium hydroxide (3 M, 5.5 mL) was added, and stirred at room temperature for 16 hours. The reaction solution was adjusted to pH about 2 with 5.0 M hydrochloric acid solution, and concentrated under reduced pressure to obtain the title product 7e (16.1 g), which was used directly in the next step without purification.

[0431] Step 5

[0432] (7-Chloro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 7

[0433] The crude compound 7e (200 mg, 255.2 μmol), 4-oxa-7-azaspiro[2.5]octane hydrochloride (49.5 mg, 330.77 μmol) and HATU (233.4 mg, 992.28 μmol) were dissolved in 10 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (256 mg, 1.98 mmol) was added and stirred for 3 hours. 60 mL of water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (80 mL×3), the organic phases were combined, washed with saturated saline solution (80 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 7 (55 mg, yield 32.7%).

[0434] MS m / z(ESI):569.1[M+1].

[0435] 1 H NMR (500 MHz, DMSO-d 6): δ8.00(s,1H),7.72(d,1H),7.61-7.47(m,4H),6.89(d,1H),4.94(d,2H),4. 05(s,1H),3.90(s,1H),3.76-3.59(m,10H),2.42(brs,4H),0.68-0.64(m,4H).

[0436] Example 8

[0437] (1-(4-(Morpholinylmethyl)phenyl)-5,5-dioxido-6-(trifluoromethyl)-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 8

[0438]

[0439]

[0440] first step

[0441] 3-((2-(Trifluoromethyl)phenyl)thio)propanoic acid 8b

[0442] Compound 8a (10.4 g, 58.3 mmol) 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. After cooling, the mixture was poured into water, and pH was adjusted to 2 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate three times, and the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title compound 8b (11.0 g) with a yield of 75.3%.

[0443] Step 2

[0444] 8-(Trifluoromethyl)thiochroman-4-one 8c

[0445] 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 solution was poured into ice water and stirred evenly. Filtered and washed with water. The solid was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent A to obtain the title compound 8c (8.0 g) with a yield of 71.8%.

[0446] Step 3

[0447] 2-(8-(Trifluoromethyl)-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 8d

[0448] Sodium ethoxide (23.5 g, 69.1 mmol, 20% w / w ethanol solution) was added to a 500 mL single-mouth bottle, 200 mL of a toluene solution of diethyl oxalate (7.6 g, 51.7 mmol) was added at 0°C, and then compound 8c (8.0 g, 34.5 mmol) was added, and stirred at room temperature for 17 h. The reaction solution was concentrated under reduced pressure, 300 mL of water was added to the residue, and dichloromethane was extracted (100 mL×2), the aqueous phase was adjusted to pH about 2 with 5M hydrochloric acid solution, and ethyl acetate was extracted (100 mL×3), the combined organic phases were washed with saturated brine (200 mL×2), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 8d (9.1 g), which was used directly in the next step without purification.

[0449] Step 4

[0450] 2-(8-(Trifluoromethyl)-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 8e

[0451] Compound 8d (9.1 g, 27.2 mmol) was dissolved in 150 mL of dichloromethane, 3-chloroperoxybenzoic acid (11.6 g, 57.2 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title compound 8e (9.8 g) with a yield of 99.3%.

[0452] Step 5

[0453] Ethyl 6-(trifluoromethyl)-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide 8f

[0454] Compound 8e (9.8 g, 26.9 mmol) was dissolved in 80 mL of ethanol, and the hydrochloride of compound 2c (7.0 g) and glacial acetic acid (20 mL) were added, and 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 was dried to obtain the title product 8f (8.0 g), with a yield of 55.5%.

[0455] Step 6

[0456] 6-(Trifluoromethyl)-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 8g

[0457] Compound 8f (8.0 g, 14.9 mmol) was dissolved in 100 mL of tetrahydrofuran, and an aqueous solution of sodium hydroxide (3 M, 5.5 mL) was added, and stirred at room temperature for 16 hours. The reaction solution was adjusted to pH about 2 with 5.0 M hydrochloric acid solution, and concentrated under reduced pressure to obtain the title product 8 g (10.5 g, purity 70%), which was directly used in the next step without purification.

[0458] Step 7

[0459] (1-(4-(Morpholinylmethyl)phenyl)-5,5-dioxido-6-(trifluoromethyl)-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 8

[0460] The crude compound 8g (200 mg, 255.2 μmol), 4-oxa-7-azaspiro[2.5]octane hydrochloride (49.5 mg, 330.77 μmol) and HATU (233.4 mg, 992.28 μmol) were dissolved in 10 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (172.9 mg, 1.34 mmol) was added and stirred for 3 hours. 60 mL of water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated saline solution (80 mL×2), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 8 (60 mg, yield 37.2%).

[0461] MS m / z(ESI):603.1[M+1].

[0462] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.01(d,1H),7.72(t,1H),7.52(t,2H),7.46-7.41(m,2H),7.19(d,1H),5.00(d,2 H),4.11(s,1H),3.95(s,1H),3.75-3.52(m,10H),2.41(brs,4H),0.69-0.65(m,4H).

[0463] Example 9

[0464] (7-Methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 9

[0465]

[0466]

[0467] first step

[0468] 3-(m-Tolylthio)propionic acid 9b

[0469] 3-Methylthiophenol 9a (10 g, 80.5 mmol) was dissolved in 100 mL of N,N-dimethylformamide, potassium carbonate (16 g, 115.7 mmol) was added, 3-bromopropionic acid was added under stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. 500 mL of water was added to quench the mixture, the aqueous phase was extracted with ethyl acetate (80 mL × 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 9b (8.94 g, yield: 56.5%), which was used directly in the next step without purification.

[0470] MS m / z(ESI):195.0[M-1].

[0471] Step 2

[0472] 7-Methylthiochroman-4-one 9c

[0473] The crude compound 9b (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 solution was carefully poured into 500 g of ice water to quench, the aqueous phase was extracted with ethyl acetate (80 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using a developing solvent system B to obtain the title compound 9c (5.17 g, yield: 63.7%).

[0474] 1 H NMR (500 MHz, CDCl 3 )δ7.30(t,1H),7.20(d,1H),7.03(d,1H),3.27-3.21(m,2H),2.93-2.85(m,2H),2.49(s,3H).

[0475] Step 3

[0476] 2-(7-Methyl-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 9e

[0477] Sodium ethoxide (20 g, 58.78 mmol, 20% w / w ethanol solution) was added to a single-mouth bottle, cooled in an ice bath, and then diethyl oxalate (4.5 g, 30.79 mmol, dissolved in 50 mL toluene) was added, and compound 9c (5.17 g, 29.00 mmol, dissolved in 50 mL toluene) was added under stirring, and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, 200 mL of water was added to quench the reaction, and the pH was adjusted to neutral with 3M hydrochloric acid aqueous solution. The aqueous phase was extracted with ethyl acetate (100 mL×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 9e (7.87 g, yield: 97.5%).

[0478] MS m / z(ESI):279.0[M+1].

[0479] Step 4

[0480] 2-(7-Methyl-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 9f

[0481] Compound 9e (7.78 g, 28.28 mmol) was dissolved in 240 mL of dichloromethane, and m-chloroperbenzoic acid (14 g, 68.96 mmol) was added in batches under ice-cooling, and stirred at room temperature for 3 hours. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using system A to obtain the title compound 9f (6.88 g, yield 78.2%).

[0482] MS m / z(ESI):310.9[M+1].

[0483] Step 5

[0484] 7-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 9g

[0485] Compound 9f (6.88 g, 22.17 mmol) and the hydrochloride of compound 2c (4.5 g, 21.71 mmol) were dissolved in 150 mL of ethanol, and glacial acetic acid (2.5 g, 41.63 mmol) was added, and the mixture was refluxed and stirred for 6 hours. After the reaction solution was cooled to room temperature, the yellow solid was filtered out, and the solid was collected and vacuum dried to obtain the crude title product 9g (14.7 g), which was directly used for the next step without purification.

[0486] MS m / z(ESI):482.2[M+1].

[0487] Step 6

[0488] 7-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 9h

[0489] The crude compound 9g (5g, 10.38mmol) was dissolved in 60mL of tetrahydrofuran, and an aqueous sodium hydroxide solution (2.5M, 10mL) was added, and the mixture was heated and stirred at 60°C for 1 hour. After the reaction was cooled to room temperature, the pH was adjusted to neutral with 3M hydrochloric acid, the organic solvent was removed under reduced pressure, and the remaining aqueous phase was lyophilized to obtain the crude title product 9h (9g), which was directly used for the next step without purification.

[0490] MS m / z(ESI):452.1[M-1].

[0491] Step 7

[0492] (7-Methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 9

[0493] The crude compound 9h (200 mg, 0.22 mmol), 4-oxa-7-azaspiro[2.5]octane hydrochloride (40 mg, 0.27 mmol) and HATU (120 mg, 0.32 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (100 mg, 0.77 mmol, 0.13 mL) was added, and the mixture was stirred for 2 hours. 150 mL of water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated saline solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 9 (32 mg, yield 26.5%).

[0494] MS m / z(ESI):549.1[M+1].

[0495] 1 H NMR (500 MHz, DMSO-d 6)δ7.84(s,1H),7.54(t,2H),7.49(d,1H),7.45(d,1H),7.38(d,1H),6.73(d,1H),4.84(d,2H),4.10-4.03(m ,1H),3.91(s,1H),3.73(d,2H),3.70-3.64(m,2H),3.64-3.56(m,6H),2.44-2.36(m,7H),0.75-0.66(m,2H), 0.66-0.58(m,2H).

[0496] Comparative Example 10

[0497] (6-Fluoro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(7-oxa-4-azaspiro[2.5]octan-4-yl)methanone 10

[0498]

[0499] Compound 1a and 7-oxa-4-azaspiro[2.5]octane hydrochloride (33 mg, 220.77 mmol, Jiangsu Aikon), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 651.77 mmol), 1-hydroxybenzotriazole (99 mg, 655.77 mmol), N,N-diisopropylethylamine (110 mg, 1.09 mmol), and 4-dimethylaminopyridine (53 mg, 437.18 mmol) were dissolved in dichloromethane (30 mL) and stirred at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V=10:1) (60 mL). The organic phases were combined, washed with water (60 mL) and saturated saline solution (60 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to give the title product 10 (25 mg, yield: 20.6%).

[0500] MS m / z(ESI):553.3[M+1].

[0501] 1 H NMR (500 MHz, DMSO-d 6 ): δ7.60-7.44(m,6H),6.65(d,1H),4.95(d,2H),3.99-3.56(m,9H),2.41(s,4H),1.27-0.72(m,7H).

[0502] Embodiment 11

[0503] (7-Chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 11

[0504]

[0505]

[0506] first step

[0507] 3-((3-Chloro-2-fluorophenyl)thio)propanoic acid 11b

[0508] 3-Chloro-2-fluorobenzenethiol 11a (8 g, 49.20 mmol, Wuxi Kehua) was dissolved in 100 mL of N,N-dimethylformamide, potassium carbonate (8.840 g, 63.96 mmol) was added, and the mixture was stirred at 60°C for 30 minutes. 3-bromopropionic acid (8.279 g, 54.12 mmol) was added, and the mixture was stirred at 60°C for 2 hours. 500 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate (200 mL×1). The pH of the aqueous phase was adjusted to about 3 with concentrated hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (300 mL×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 11b (11.166 g, yield: 96.7%), which was used directly in the next step without purification.

[0509] Step 2

[0510] 7-Chloro-8-fluorothiochroman-4-one 11c

[0511] The 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 solution was carefully poured into 500 mL of ice water for quenching, the aqueous phase was extracted with ethyl acetate (200 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 11c (8.731 g, yield: 85.1%), which was used directly in the next step without purification.

[0512] Step 3

[0513] 2-(7-Chloro-8-fluoro-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 11d

[0514] Sodium ethoxide (27.423 g, 80.60 mmol, 20% w / w ethanol solution, TCI) and 125 mL toluene were added to a single-mouth bottle, cooled in an ice bath, and then diethyl oxalate (8.834 g, 60.45 mmol) was added, and crude compound 11c (8.731 g, 40.30 mmol) was added under stirring, and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, 600 mL of water was added to quench the reaction, and the pH was adjusted to about 3 with concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate (250 mL×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, yield: 93.4%).

[0515] MS m / z(ESI):316.9[M+1].

[0516] Step 4

[0517] 2-(7-Chloro-8-fluoro-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 11e

[0518] Compound 11d (11.919 g, 37.63 mmol) was dissolved in 130 mL of dichloromethane, and m-chloroperbenzoic acid (19.100 g, 94.08 mmol) was added in batches under ice-cooling, and stirred at room temperature for 17 hours. The insoluble matter 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%).

[0519] MS m / z(ESI):347.0[M-1].

[0520] Step 5

[0521] 7-Chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 11f

[0522] Compound 11e (11.5 g, 32.98 mmol) and the hydrochloride of compound 2c (10.024 g) were dissolved in 250 mL of ethanol, and glacial acetic acid (3.961 g, 65.96 mmol) was added, and the mixture was refluxed and stirred 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×4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude title product 11f (16 g, yield: 93.3%), which was directly used for the next step without purification.

[0523] MS m / z(ESI):520.0[M+1].

[0524] Step 6

[0525] 7-Chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 11g

[0526] The crude compound 11f (16 g, 30.77 mmol) was dissolved in 250 mL of tetrahydrofuran, and an aqueous sodium hydroxide solution (2.5 M, 62 mL) was added and stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 3 with 3 M hydrochloric acid and concentrated under reduced pressure to obtain the crude title product 11 g (15 g, yield: 99.1%), which was directly used for the next step without purification.

[0527] MS m / z(ESI):491.9[M+1].

[0528] Step 7

[0529] (7-Chloro-6-fluoro-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 11

[0530] The crude compound 11g (506mg, 0.52mmol), 4-oxa-7-azaspiro[2.5]octane hydrochloride (80mg, 0.53mmol) and HATU (240mg, 0.63mmol) were dissolved in 25mL N,N-dimethylformamide, and N,N-diisopropylethylamine (340mg, 2.63mmol) was added, and the mixture was stirred for 17 hours. 50mL of saturated sodium bicarbonate solution was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, the filtrate was concentrated under reduced pressure, and the title product 11 (72.6mg, yield: 23.6%) was obtained by silica gel column chromatography with eluent system A.

[0531] MS m / z(ESI):587.0[M+1].

[0532] 1 H NMR (500 MHz, DMSO-d 6 )δ7.85(s,1H),7.53-7.46(m,4H),6.68-6.66(m,1H),5.05-5.03(m,2H),4.06-3.47(m,12H),2.50-2.42(m,4H),0.73-0.60(m,4H).

[0533] Example 12

[0534] (9-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 12

[0535]

[0536] first step

[0537] 5-Methylthiochroman-4-one 12a

[0538] The crude compound 9b (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 solution was carefully poured into 500 g of ice water to quench, and the liquid was separated. The aqueous phase was extracted with ethyl acetate (80 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using a developing solvent system B to obtain the title compound 12a (5.17 g, yield: 41.6%).

[0539] 1 H NMR (500 MHz, CDCl 3 )δ7.30(t,1H),7.20(d,1H),7.03(d,1H),3.27-3.21(m,2H),2.93-2.85(m,2H),2.49(s,3H).

[0540] Step 2

[0541] 2-(5-methyl-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 12b

[0542] Sodium ethoxide (13 g, 38.21 mmol, 20% w / w ethanol solution) was added to a single-mouth bottle, cooled in an ice bath, and then diethyl oxalate (3.0 g, 20.53 mmol, dissolved in 50 mL toluene) was added, and compound 12a (3.38 g, 18.93 mmol, dissolved in 50 mL toluene) was added under stirring, and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, 200 ml of water was added to quench the reaction, and the pH was adjusted to neutral with a 3M aqueous hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate (100 mL×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 12b (3.66 g, yield: 69.56%), which was directly used for the next step without purification.

[0543] MS m / z(ESI):279.0[M+1].

[0544] Step 3

[0545] 2-(5-methyl-1,1-dioxido-4-oxothiochroman-3-yl)-2-oxoacetic acid ethyl ester 12c

[0546] Compound 12b (3.66 g, 13.17 mmol) was dissolved in 50 mL of dichloromethane, and m-chloroperbenzoic acid (6 g, 29.55 mmol, content 85%) was added in batches under ice-cooling, and stirred at room temperature for 3 hours. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using system A to obtain the crude title compound 12c (7.3 g, crude product).

[0547] MS m / z(ESI):310.9[M+1].

[0548] Step 4

[0549] 9-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid ethyl ester 5,5-dioxide 12d

[0550] The crude compound 12c (7.3 g, 12.94 mmol) and the hydrochloride of compound 2c (3.6 g) were dissolved in 50 mL of ethanol, and glacial acetic acid (1.5 g, 24.98 mmol) was added, and the mixture was refluxed and stirred for 6 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filter cake was collected and vacuum dried to obtain the title product 12d (6.8 g), which was directly used for the next step without purification.

[0551] MS m / z(ESI):482.2[M+1].

[0552] Step 5

[0553] 9-Methyl-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 12e

[0554] The crude compound 12d (1.35 g, 1.54 mmol) was dissolved in 15 mL of tetrahydrofuran, and an aqueous sodium hydroxide solution (2.5 M, 3 mL) was added, and the mixture was heated and stirred at 60°C for 1 hour. After the reaction was cooled to room temperature, the pH was adjusted to neutral with 3 M hydrochloric acid, the organic solvent was removed under reduced pressure, and the remaining aqueous phase was lyophilized to obtain the crude title product 12e (2.2 g), which was directly used for the next step without purification.

[0555] MS m / z(ESI):452.1[M-1].

[0556] Step 6

[0557] (9-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxido-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)(4-oxa-7-azaspiro[2.5]octan-7-yl)methanone 12

[0558] The crude compound 12e (200 mg, 0.22 mmol), 4-oxa-7-azaspiro[2.5]octane hydrochloride (45 mg, 0.30 mmol) and HATU (150 mg, 0.40 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (150 mg, 1.16 mmol, 0.19 mL) was added and stirred for 2 hours. 150 mL of water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated saline solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 12 (62 mg, yield 43.7%).

[0559] MS m / z (ESI): 549.1 [M+H].

[0560] 1 H NMR (500 MHz, DMSO-d 6 )δ7.89(d,1H),7.64(t,1H),7.53(d,1H),7.45(t,2H),7.27(d,2H),4.79(s,2H),4.06(t,1H ),3.93(s,1H),3.79-3.47(m,9H),3.29(s,1H),2.37(s,4H),1.61(d,3H),0.75-0.52(m,4H).

[0561] Test example:

[0562] Biological evaluation

[0563] Test Example 1: Inhibitory activity and selectivity test of the disclosed compounds on PI3Kδ enzyme

[0564] 1. Purpose of the experiment

[0565] The purpose of this experiment is to test the inhibitory effect and selectivity of compounds on PI3Kδ enzymatic activity. 50 Size evaluation of the in vitro activity of compounds.

[0566] 2. Experimental Principle

[0567] In this experiment, ADP-Glo TMKinase Assay Kit: Under the action of enzyme, the substrate is phosphorylated and ADP is produced. ADP-Glo ​​Reagent is added to remove the unreacted ATP in the reaction system, and Kinase detection reagent is used to detect the ADP produced by the reaction. In the presence of the compound, the inhibition rate of the compound is calculated by measuring the signal value.

[0568] 3. Experimental Materials

[0569] 1. Instrument

[0570] Instrument Name Supply Company model Centrifuge Eppendorf 5430 ELISA reader PerkinElmer Envision, SN.1050214 Echo 550 Labcyte Echo 550

[0571] 2. Reagents and consumables

[0572] Reagent name Supply Company Part Number PIK3CD / PIK3R1 Carna 11-103 PI103 selleckchem S1038 DMSO Sigma D8418-1L 384-well white plate PerkinElmer 6007290

[0573] IV. Experimental Methods

[0574] The test compound was tested at a starting concentration of 10000nM, 3-fold dilution, 11 concentrations, and duplicate wells. The solution was diluted to 11 different concentrations of 100-fold final concentration in a 384-well plate. 50nL was transferred to the compound wells of the 384-well plate using Echo; 50nL of DMSO was added to the negative control wells. A kinase solution with a final concentration of 2 was prepared using 1× Kinase buffer. 2.5μL of a kinase solution with a final concentration of 2 was added to the compound wells; 2.5μL of 1× Kinase buffer was added to the negative control wells. Centrifuge at 1000rpm for 30 seconds, shake and mix, and incubate at room temperature for 10 minutes. A mixed solution of ATP and substrate P1P2 with a final concentration of 2 was prepared using 1× Kinase buffer. 2.5μL of a mixed solution of ATP and substrate with a final concentration of 2 was added to start the reaction. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 120 minutes. Add 5 μL ADP-Glo ​​reagent, centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 40 minutes. Add 10 μL Kinase Detection Reagent, centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 30 minutes. Read the luminescence value RLU using Envision microplate reader.

[0575] 5. Data Analysis

[0576] The IC of the inhibitory activity of the compounds was calculated using Graphpad Prism software 50 The results are shown in Table 1 below.

[0577] Table 1 Inhibitory and selective activity data of the disclosed compounds on PI3Kδ enzyme (unit: nM)

[0578] Example No. <![CDATA[PI3Kδ enzyme IC 50 > <![CDATA[PI3Kα enzyme IC 50 > <![CDATA[PI3Kβ enzyme IC 50 > <![CDATA[PI3Kγ enzyme IC 50 > 1 13 467.6 1316.0 6210.0 2 18.4 - - - 3 5.6 - - - 4 7.9 - - - 5 19 2329 2791 >10000 6 68 2570 7058 >10000 7 26.5 1523 1743 >10000 9 25.0 1761 1551 >10000 11 10.5 441 736 8918 12 5.8 - - - 10 (Comparative example) >10000 - - -

[0579] Conclusion: Compared with the control example, the disclosed compounds have stronger inhibitory activity and selectivity against PI3Kδ enzyme.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: R a , R b , R c , R d , R e and R f are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl and halogen; R 0 , R 1 Together with the carbon atom to which they are attached, they form a spirocyclopropyl group on the attached heterocyclic ring; R 5 is phenyl, wherein the phenyl is replaced by a 5- or 6-membered monocyclic heterocyclic group C 1-6 Alkyl is substituted, the 5 or 6-membered monocyclic heterocyclic group C 1-6 Alkyl is optionally selected from halogen, C 1-6 Alkyl and C 1-6 is substituted by one or more substituents in a haloalkyl group; R 2 and R 4 is a hydrogen atom; R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkyl halide, cyano and -OR i ; R i Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Haloalkyl; n is 1; q is 0, 1, 2, 3 or 4.

2. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, wherein the phenyl is substituted by morpholinylmethyl.

3. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 for 4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof: in: R' is a hydrogen atom; m is 0, 1, 2 or 3; R 10 is a hydrogen atom; R 11 is a hydrogen atom; Each R 12 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; w is 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, 4, 5, or 6; R a -Rf, R 2 -R 4 and q as defined in claim 1.

5. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently selected from hydrogen, halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl.

6. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

7. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 For F.

8. The compound represented by the general formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 12 A hydrogen atom.

9. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a -R f are each independently a hydrogen atom. 10 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein q is 1 or 2.

11. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein q is 1.

12. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

13. A method for preparing the compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound of general formula (IA) or a pharmaceutically acceptable salt thereof reacts with the compound of general formula (IB) or a pharmaceutically acceptable salt thereof to obtain the compound of general formula (I) or a pharmaceutically acceptable salt thereof, Where R 0 -R 5 , R a -R f , n and q are as defined in claim 1.

14. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a medicament for inhibiting PI3Kδ.

16. Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 in the preparation of a medicament for treating and / or preventing inflammatory diseases, autoimmune diseases and cancer.

17. The use according to claim 16, wherein the cancer is 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 tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma.

18. The use according to claim 17, 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; 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; the lung cancer is non-small cell lung cancer or small cell lung cancer; the myeloma is multiple myeloma (MM); the liver cancer is hepatocellular carcinoma; the head and neck tumor is head and neck squamous cell carcinoma; the sarcoma is osteosarcoma or soft tissue sarcoma; the colorectal cancer is colon cancer or rectal cancer.

19. The method of claim 16, wherein the autoimmune disease is selected from the group consisting of 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-person syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia, and Wegener's granulomatosis.

20. The use according to claim 19, wherein the lupus is lupus erythematosus or systemic lupus erythematosus; and the pemphigus is pemphigus vulgaris.

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