CN113754685A

CN113754685A - Dihydrothiochromene pyrazole derivative, preparation method and medical application thereof

Info

Publication number: CN113754685A
Application number: CN202110608102.1A
Authority: CN
Inventors: 陆标; 王玉明; 桂斌; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-06-02
Filing date: 2021-06-01
Publication date: 2021-12-07
Anticipated expiration: 2041-06-01
Also published as: CN113754685B

Abstract

The disclosure relates to dihydrothiochromenopyrazole derivatives, a preparation method thereof and application thereof in medicines. Specifically, the disclosure relates to a dihydrothiochromenopyrazole derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, in particular application of the derivative as a PI3K delta inhibitor and application of the derivative in preparation of drugs for treating conditions or disorders improved by inhibition of PI3K delta.

Description

Dihydrothiochromene pyrazole derivative, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicine, and relates to a dihydrothiochromenopyrazole derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, in particular application of the derivative as a PI3K delta inhibitor and application of the derivative in preparation of a medicament for treating a disease state or a disorder improved by inhibition of PI3K delta.

Background

Phosphatidylinositol 3-kinase (PI 3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, and is involved in regulating the processes of cell proliferation, differentiation, apoptosis, angiogenesis and the like. Abnormal activation of PI3K is closely related to the development of various tumors, and different types of PI3K play different functions. There are four subtypes of PI3K, α, β, γ and δ, among which PI3K δ is mainly present in immune cells and blood cells and is closely related to the development of immunity, hematologic tumors and inflammation (Cell,170(4), 605-635).

PI3K δ is mainly expressed in immune cells and hematopoietic cells, and is involved in BCR signaling in B cells, controlling the development and maturation of B cells in the body. When an antigen stimulates the organism, specific surface immunoglobulin Ig on the surface of BCR can be combined with the antigen, so that ITAM phosphorylation of an intracellular segment of a CD79A/B complex is caused, and the phosphorylated ITAM can collect and activate SYK and further activate BTK and a downstream molecule PLC gamma 2 thereof. Activated SYK binds to P85 subunit of PI3K δ, activates PI3K δ, promotes PIP3 production, and PIP3 produced is capable of recognizing the N-terminal domain of BTK and interacting with it to mediate BTK recruitment to the membrane, thereby activating BTK-mediated B cell signaling and inducing expression of a plurality of related genes. In addition, phosphorylated CD19 also recruits PI 3K. delta. on cell membranes, activates PI 3K. delta., catalyzes PIP2 to PIP3, activates AKT, and promotes cell proliferation, migration, apoptosis, etc. (N Engl J Med,379, 2052-2062). In addition to regulating B cell function, recent studies have reported that PI3K δ activation promotes the development, maturation and recruitment of Treg cells (Cancer Immunol Res,2,1080-. Inhibition of PI3K δ promoted the proliferation and survival of CD8+ memory T cells (Cancer Res,77, 4135-4145). Therefore, PI3K delta is an ideal target for treating B cell lymphoma, and the development of selective PI3K delta inhibitors as medicines for treating hematological tumors is increasingly emphasized.

Idelalisib is the first approved PI3K δ selective inhibitor marketed and approved for the treatment of Chronic Lymphocytic Leukemia (CLL), Follicular Lymphoma (FL) and Small Lymphocytic Lymphoma (SLL) in 2014. Duvelisib (acting on PI3K δ and γ) was subsequently approved for the treatment of Chronic Lymphocytic Leukemia (CLL) and Follicular Lymphoma (FL) in 2018. Although PI3K δ inhibitors have shown excellent results in the treatment of these hematological tumors, early inhibitors often show poor selectivity for PI3K kinase, and thus clinically have seen a number of drug-related hepatotoxicity and gastrointestinal toxicity. In order to further reduce the potential side effects of PI3K δ inhibitors, a number of companies have actively developed second-generation highly selective PI3K δ inhibitors in recent years, typically parsaclibib, ME-401 and IOA-244, which are currently in different clinical stages.

IOA-24 is a second generation PI3K δ inhibitor (WO2011058149a1, WO2014121901a1) developed by the ioctura corporation, which is an ATP non-competitive inhibitor compared to the traditional PI3K δ inhibitor, which results in a high selectivity of the drug for inhibition of the PI3K δ subtype.

Considering that the side effects of the first generation PI3K δ inhibitors currently on the market are all significant, limiting the use of this type of drugs in a larger patient population, there is a significant unmet medical need to develop second generation highly selective PI3K δ inhibitors in the relevant patient population.

Relevant patents disclosed in the prior art include WO2011058149a1, WO2015196759a1, WO2015196335a1, WO2014209980a1, WO2010049366a1 and the like.

Disclosure of Invention

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

wherein:

ring a is a 5-6 membered heterocyclyl or heteroaryl;

W¹is a carbon or nitrogen atom;

R⁵selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by a group selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹、-NR⁶SO₂R⁹And R' is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl;

R¹the same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxy, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸Cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, - (CH)₂)_sNR⁷R⁸and-OR⁹Is substituted with one or more substituents of (1); when m is greater than or equal to 2, two R¹Spiro or bridged ring systems may be formed on the oxygen-containing heterocycle;

R²the same or different, each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl and heteroarylalkyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a substituent selected from the group consisting of alkyl, haloalkyl, halogen, cyano, nitro, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹and-NR⁶SO₂R⁹Is substituted with one or more substituents of (1);

R³are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹、-NR⁶SO₂R⁹Cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, cyano, nitro, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹and-NR⁶SO₂R⁹Is substituted with one or more substituents of (1);

R⁴the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and- (C)H₂)_sNR⁷R⁸Is substituted with one or more substituents of (1);

R⁶selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, and aryl groups, wherein said alkyl groups, cycloalkyl groups, and aryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl groups, alkoxy groups, oxo groups, halogens, amino groups, cyano groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R⁷and R⁸Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

or R⁷And R⁸Together with the nitrogen atom to which they are attached form a heterocyclic group, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R⁹selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, - (CH)₂)_sNR⁷R⁸Cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;

m is 0, 1,2,3, 4 or 5;

n is 1 or 2;

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

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

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

t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a five-membered heteroaryl.

In some preferred embodiments of the present disclosure, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein W¹、W²、W³And W⁴The same or different, each independently selected from carbon atoms or nitrogen atoms, provided that they are not carbon atoms at the same time;

R¹-R⁵m, n, q and r are as defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹Is a nitrogen atom.

In some preferred embodiments of the present disclosure, a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹And W³Is a nitrogen atom, W²Is a carbon atom, W⁴Is a carbon atom or a nitrogen atom.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IIa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

W⁴is a carbon atom or a nitrogen atom;

R¹-R³、R⁵m and q are as defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹、W³And W⁴Is a nitrogen atom, W²Is a carbon atom; or W²Is a nitrogen atom, W¹Is a carbon atom, W³And W⁴Is a carbon atom or a nitrogen atom.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III) or (IIIa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is¹-R³、R⁵M and q are as defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IIIaa) or (IIIab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is^xIs halogen;

R^yselected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with a group selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and- (CH)₂)_sNR⁷R⁸Is substituted with one or more substituents of (1);

R¹-R³、R⁵、R⁷、R⁸m, s and q are as defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa) or (IIIab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, or salt thereof, and a pharmaceutical composition containing said composition, and a pharmaceutical composition containing said composition, and a pharmaceutical composition containing a pharmaceutical composition, and a pharmaceutical composition containing a pharmaceutical composition, and a⁵Selected from the group consisting of heterocyclyl, aryl and heteroaryl, each independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹、-NR⁶SO₂R⁹And R 'is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, each R' is independently optionally substituted with one OR more substituents selected from the group consisting of halogen, alkyl, haloalkyl, and-OR⁹Is substituted with one or more substituents of (1);

R⁶-R⁹s and t are as defined in formula (I).

Preferably, R⁵Selected from aryl or heteroaryl, each independently optionally selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹、-NR⁶SO₂R⁹And R 'is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, each R' is independently optionally substituted with one OR more substituents selected from the group consisting of halogen, alkyl, haloalkyl, and-OR⁹Is substituted with one or more substituents of (1);

R⁶-R⁹s and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa) or (IIIab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, or salt thereof, and a pharmaceutical composition containing said composition, and a pharmaceutical composition containing said composition, and a pharmaceutical composition containing a pharmaceutical composition, and a pharmaceutical composition containing a pharmaceutical composition, and a⁵Selected from the group consisting of heterocyclyl, aryl and heteroaryl, each independently optionally substituted with R'; r' is selected from cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl and haloalkyl.

Preferably, R⁵Selected from aryl or heteroaryl, each independently optionally substituted with R', selected from cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, each independently optionally substituted with one or more substituents selected from halogen, alkyl and haloalkyl.

Further preferably, R⁵Selected from aryl, said aryl being optionally substituted with heterocyclylalkyl, said heterocyclylalkyl being optionally selectedSubstituted with one or more substituents selected from halogen, alkyl and haloalkyl.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III) or (IIIa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV) or (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

R¹⁰The same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and- (CH)₂)_sNR⁷R⁸Is substituted with one or more substituents of (1);

R¹¹the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, nitro, - (CH)₂)_sNR⁷R⁸Cycloalkyl, cycloalkyloxy and cycloalkylalkyl;

R¹²the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl; when u is 2 or more, two R¹²Spiro or bridged ring systems can be formed on the morpholine ring;

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

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

R¹-R³、R⁷-R⁹s, m and q are as defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (IIIaa) or (IIIab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (iva) or (iva), or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is^xIs halogen;

R¹-R³、R⁷、R⁸、R¹⁰-R¹²q, s, w, u and m are as defined in formula (IV).

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa) or (IIIab), or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V), (Va), (Vaa) or (Vab), or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R^xis halogen;

ring B is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

j is 1,2,3, 4 or 5;

In some preferred embodiments of the present disclosure, a compound of formula (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 6-membered aryl, 5-6-membered heteroaryl, and 5-6-membered heterocyclyl; preferably, ring B is a 6-membered aryl or 6-membered heterocyclyl; further preferred is a phenyl group or a piperidyl group.

In some preferred embodiments of the present disclosure, a compound of formula (IIIab), (iva) or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^yIs selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; preferably, the first and second electrodes are formed of a metal,R^yis selected from C_1-6Alkyl radical, C_1-6Haloalkyl and 3 to 6-membered cycloalkyl; more preferably methyl or cyclopropyl.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition containing said composition¹The same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸And cycloalkyl, wherein said alkyl, cycloalkyl, cycloalkylalkyl and cycloalkyloxy are each independently optionally substituted with one OR more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano and-OR⁹Is substituted with one or more substituents of (1); when m is greater than or equal to 2, two R¹Spiro or bridged ring systems may be formed on the oxygen-containing heterocycle;

preferably, R¹The same OR different, are each independently selected from the group consisting of hydrogen, alkyl, halogen, alkoxy and haloalkoxy, wherein said alkyl is optionally substituted with a substituent selected from the group consisting of halogen, cyano and-OR⁹Is substituted with one or more substituents of (1);

more preferably, R¹Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; further preferred is hydrogen or methyl.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition containing said composition²The same or different, are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl and cycloalkylalkyl, wherein the alkyl and cycloalkyl are independently optionally substituted with one or more substituents selected from alkyl, haloalkyl, haloElement, cyano and-OR⁹Is substituted with one or more substituents of (1);

preferably, R²Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; further preferred is hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition containing said composition³Are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, - (CH)₂)_sNR⁷R⁸and-OR⁹；

Preferably, R³The same or different, each independently selected from hydrogen, halogen, halogenated C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6An alkyl group.

More preferably, R³Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁴The same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸and-OR⁹；

Preferably, R⁴Selected from hydrogen, halogen, C_1-6Alkyl and C_3-8A cycloalkyl group;

further preferably, R⁴Is hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (IVaa), (IVab), (V), (Va), (Vaa) or (Vab), or a tautomer thereofA structure, meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁶Selected from the group consisting of hydrogen atoms, alkyl groups and cycloalkyl groups, wherein said alkyl and cycloalkyl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, hydroxy and hydroxyalkyl;

preferably, R⁶Selected from hydrogen atoms and C_1-6An alkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition containing said composition⁷And R⁸Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a cycloalkyl group; or R⁷And R⁸Together with the nitrogen atom to which they are attached form a heterocyclic group, said heterocyclic group being optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, hydroxyalkyl and cycloalkyl;

preferably, R⁷And R⁸Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C_1-6Alkyl and C_1-6A haloalkyl group; or R⁷And R⁸Together with the nitrogen atom to which they are attached form a heterocyclic group, said heterocyclic group being optionally selected from C_1-6Alkyl radical, C_1-6Alkoxy and halogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and wherein R is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition containing said composition⁹Independently selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; wherein saidEach of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, cyano and amino;

preferably, R⁹Independently selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, and cycloalkyl groups; wherein said alkyl and cycloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, and haloalkyl.

Further preferably, R⁹Is C_1-6An alkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹⁰The same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸and-OR⁹；

Preferably, R¹⁰Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; further preferred is hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹¹The same or different, each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano and- (CH)₂)_sNR⁷R⁸；

Preferably, R¹¹Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; further preferred is hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (IV), (IVa), (IVaa), (I)Vab), (V), (Va), (Vaa) or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹²The same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸and-OR⁹；

Preferably, R¹²Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; further preferred is hydrogen or methyl.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or2, preferably 0 or 1, more preferably 0.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1, preferably 0 or 1, more preferably 0.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa) or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1,2 or 3, preferably 1.

In some preferred embodiments of the present disclosure, a compound of formula (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein u is 0, 1,2, or 3, preferably 0 or 1, more preferably 0.

In some preferred embodiments of the present disclosure, a compound of formula (IV), (IVa), (V), (Va), (Vaa), or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein w is 0, 1, or2, preferably 0.

In some preferred embodiments of the present disclosure, a compound of formula (V), (Va), (Vaa) or (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein j is 1 or2, preferably 1.

In some preferred embodiments of the present disclosure, a compound of formula (V) or (Va), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-membered aryl or 6-membered heterocyclyl; r¹Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; m is 0 or 1; r²Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; r³The same or different, each independently selected from hydrogen, halogen, halogenated C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6An alkyl group; q is 1; r¹⁰Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; w is 0, 1 or 2; r¹¹Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; j is 1 or 2; r¹²Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; u is 0 or 1.

In some preferred embodiments of the present disclosure, a compound of formula (V)aa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R^xIs halogen; ring B is a 6-membered aryl or 6-membered heterocyclyl; r¹Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; m is 0 or 1; r²Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; r³The same or different, each independently selected from hydrogen, halogen, halogenated C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6An alkyl group; q is 1; r¹⁰Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; w is 0, 1 or 2; r¹¹Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; j is 1 or 2; r¹²Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; u is 0 or 1.

In some preferred embodiments of the present disclosure, a compound of formula (Vab), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^yIs selected from C_1-6Alkyl radical, C_1-6Haloalkyl and 3 to 6-membered cycloalkyl; ring B is a 6-membered aryl or 6-membered heterocyclyl; r¹Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; m is 0 or 1; r²Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group; r³The same or different, each independently selected from hydrogen, halogen, halogenated C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6An alkyl group; q is 1; r¹⁰Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; w is 0, 1 or 2; r¹¹Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; j is 1 or 2; r¹²Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group; u is 0 or 1.

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

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a compound represented by formula (IIIA) or (IIIaA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is¹-R³、R⁵M and q are as defined in formula (III).

Another aspect of the present disclosure relates to a compound of formula (IVA) or (IVA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is¹-R³、R¹⁰-R¹²Q, w, m and u are as defined in formula (IV).

Another aspect of the present disclosure relates to a compound of formula (VA) or (VaA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein the ring B, R¹-R³、R¹⁰-R¹²Q, w, j, m and u are as defined in formula (V).

Typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method of preparing a compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting a compound of formula (IIIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (IIIB) or a salt thereof, to give a compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein L is a leaving group selected from the group consisting of alkylthio, alkoxy, halogen, hydroxy and mercapto (when hydroxy or mercapto, the enolic interconversion is to a ketone or thione); preferably alkoxy, more preferably methoxy;

R¹-R³、R⁵q and m are as defined in formula (III).

Another aspect of the present disclosure relates to a process for preparing a compound of formula (IIIa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting a compound of formula (IIIaA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to a ring closure reaction to obtain a compound of formula (IIIa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R is¹-R³、R⁵Q and m are as defined in formula (IIIa).

Another aspect of the present disclosure relates to a process for preparing a compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting a compound of formula (IVA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (IIIB) or a salt thereof to give a compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

R¹-R³、R¹⁰-R¹²q, w and u are as defined in formula (IV).

Another aspect of the present disclosure relates to a process for preparing a compound of formula (IVa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting a compound of formula (IVAA) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof to a ring closure reaction to obtain a compound of formula (IVa) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof,

wherein R is¹-R³、R¹⁰-R¹²Q, w, u and m are as defined in formula (IVa).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting a compound of formula (VA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (VB) or a salt thereof, to give a compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

ring B, R¹-R³、R¹⁰-R¹²Q, w, j, m and u are as defined in formula (V).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (Va) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting a compound of formula (VaA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to ring closure to obtain a compound of formula (Va) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein the ring B, R¹-R³、R¹⁰-R¹²Q, w, u, j and m are as defined in formula (Va).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) of the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of general formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting PI3K δ.

The disclosure further relates to the use of a compound of general formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a PI3K δ -mediated disease.

The present disclosure further relates to the use of a compound of general formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of inflammatory diseases, autoimmune diseases, cancer and related diseases, preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, biliary tract cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, cervical cancer, pancreatic cancer, a pharmaceutically acceptable salt thereof, Ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, preferably selected from chronic lymphocytic leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML) and hairy cell leukemia, preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-hodgkin's lymphoma (NHL), lymphoplasmacytoma, marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma and diffuse large B-cell lymphoma, said lung cancer is preferably non-small cell lung cancer or small cell lung cancer, said myeloma is preferably Multiple Myeloma (MM), said autoimmune disease is preferably selected from asthma, rheumatoid arthritis, Acute Disseminated Encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behcet's disease, celiac disease, anti-glutamine transaminase, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, goodpasture's syndrome, Graves 'disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa disease, Kawasaki disease, glomerulonephritis type A, immune thrombocytopenic purpura, Idiopathic Thrombocytopenic Purpura (ITP), interstitial cystitis, lupus nephritis, membranous nephropathy, mixed connective tissue disease, scleroderma, Multiple Sclerosis (MS), myasthenia gravis, narcolepsy, neuromuscular sclerosis, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo and Wegener's granuloma, 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 squamous cell carcinoma, the sarcoma is preferably osteosarcoma or soft tissue sarcoma and the colorectal cancer is preferably colon cancer or rectal cancer.

The present disclosure also relates to a method of inhibiting PI3K δ comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method for the treatment and/or prevention of PI3K δ -mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing inflammatory diseases, autoimmune diseases, cancer and related diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, biliary tract cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, preferably selected from chronic lymphocytic leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), and hairy cell leukemia, the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-hodgkin's lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma and diffuse large B-cell lymphoma, the lung cancer is preferably non-small cell lung cancer or small cell lung cancer, the myeloma is preferably Multiple Myeloma (MM), the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, Acute Disseminated Encephalomyelitis (ADEM), addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, behcet's disease, celiac disease, anti-glutamine transaminase, anti-phospholipid antibody syndrome (APS), Chagas ' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, goodpasture's syndrome, Graves ' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis purulenta, Kawasaki disease, Tokyo-globulina nephropathy, immune thrombocytopenic purpura, Idiopathic Thrombocytopenic Purpura (ITP), interstitial cystitis, lupus nephritis lupus, membranous nephropathy, mixed connective tissue disease, maculopathy, Multiple Sclerosis (MS), myasthenia gravis, narcolepsy, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, Sjogren's syndrome, stiff person's syndrome, chronic arterial disease, Graves's disease, Graves ' disease, and ' disease, Vitiligo 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.

The present disclosure further relates to a compound of general formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure also relates to compounds of general formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a PI3K δ inhibitor.

The disclosure also relates to compounds of general formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a PI3K δ mediated disease.

The present disclosure also relates to compounds of general formula (I), (II), (IIa), (III), (IIIa), (IIIaa), (IIIab), (IV), (IVa), (V), (Va), (Vaa), (Vab) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of inflammatory diseases, autoimmune diseases, cancer and related diseases, preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, paediatric tumors, cervical cancer, ovarian cancer, urinary bladder cancer, Urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, said leukemia being preferably selected from chronic lymphocytic leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML) and hairy cell leukemia, said lymphoma being preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, perinodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma and diffuse large B-cell lymphoma, the lung cancer is preferably non-small cell lung cancer or small cell lung cancer, the myeloma is preferably Multiple Myeloma (MM), the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, Acute Disseminated Encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behcet's disease, celiac disease, anti-transglutaminase, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, goodpasture's syndrome, Graves 'disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, glomerulonephritis, immune thrombocytopenic purpura, autoimmune diseases, and autoimmune diseases, Idiopathic Thrombocytopenic Purpura (ITP), interstitial cystitis, lupus nephritis, membranous nephropathy, mixed connective tissue disease, hard spots, Multiple Sclerosis (MS), myasthenia gravis, narcolepsy, neuromuscular rigidity, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo 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.

The PI3K δ -mediated diseases described in the present disclosure are selected from inflammatory diseases, autoimmune diseases, cancer and related diseases; preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, biliary tract cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, preferably selected from chronic lymphocytic leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), and hairy cell leukemia, the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-hodgkin's lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma and diffuse large B-cell lymphoma, the lung cancer is preferably non-small cell lung cancer or small cell lung cancer, the myeloma is preferably Multiple Myeloma (MM), the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, Acute Disseminated Encephalomyelitis (ADEM), addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, behcet's disease, celiac disease, anti-glutamine transaminase, anti-phospholipid antibody syndrome (APS), Chagas ' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, goodpasture's syndrome, Graves ' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis purulenta, Kawasaki disease, Tokyo-globulina nephropathy, immune thrombocytopenic purpura, Idiopathic Thrombocytopenic Purpura (ITP), interstitial cystitis, lupus nephritis lupus, membranous nephropathy, mixed connective tissue disease, maculopathy, Multiple Sclerosis (MS), myasthenia gravis, narcolepsy, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, Sjogren's syndrome, stiff person's syndrome, chronic arterial disease, Graves's disease, Graves ' disease, and ' disease, Vitiligo 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.

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

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

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

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

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

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

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health 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 regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1,2,3, 4, 5,6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 (e.g., 1,2,3, 4, 5, or 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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 and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

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

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

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

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused ring alkyls. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocychc ring as described aboveOn a cycloalkyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples include

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

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

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but which does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4, 5,6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably from 3 to 8 ring atoms (e.g., 3,4, 5,6, 7 and 8), of which 1-3 (e.g., 1,2 and 3) are heteroatoms; more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group which shares a single atom (referred to as the spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, said substituents preferably being independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system 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 membered (e.g. 5,6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

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

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

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

The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "cycloalkylalkyl" refers to cycloalkyl-alkyl-wherein cycloalkyl and alkyl are as defined above.

The term "heterocyclylalkyl" refers to heterocyclyl-alkyl-, wherein heterocyclyl and alkyl are as defined above.

The term "arylalkyl" refers to aryl-alkyl-wherein aryl and alkyl are as defined above.

The term "heteroarylalkyl" refers to heteroaryl-alkyl-, wherein heteroaryl and alkyl are as defined above.

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" or "oxo" means "═ O".

The term "carbonyl" refers to C ═ O.

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

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure may also comprise isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure except that "deuterium" or "tritium" is substituted for hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-，¹³C-, or¹⁴C-enriched carbon (C¹¹C-，¹³C-, or¹⁴C-carbon labeling;¹¹C-，¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The disclosure also includes various deuterated forms of the compounds. Meaning that each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

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

"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

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

By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.

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

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

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

Synthesis of the Compounds of the disclosure

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

scheme one

The preparation method of the compound shown in the general formula (III) or the salt thereof, or the preparation method of the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

R¹-R³、R⁵q and m are as defined in formula (III).

Scheme two

The invention discloses a method for preparing a compound shown as a general formula (IV) or a salt thereof, or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

R¹-R³、R¹⁰-R¹²q, w and u are as defined in formula (IV).

Scheme three

The preparation method of the compound shown in the general formula (IIIa) or the salt thereof, or the preparation method of the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof, comprises the following steps:

a compound of the general formula (IIIaA) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and ammonium acetate are subjected to ring closure reaction to obtain a compound of the general formula (IIIa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof,

wherein R is¹-R³、R⁵Q and m are as defined in formula (IIIa).

Scheme four

The preparation method of the compound shown in the general formula (IVa) or the salt thereof, or the preparation method of the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

a compound of the general formula (IVAA) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof is subjected to a ring closure reaction with ammonium acetate to obtain a compound of the general formula (IVa) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof,

wherein R is¹-R³、R¹⁰-R¹²Q, w, u and m are as defined in formula (IVa).

Scheme five

The preparation method of the compound shown in the general formula (V) or the salt thereof, or the preparation method of the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

ring B, R¹-R³、R¹⁰-R¹²Q, w, j, m and u are as defined in formula (V).

Scheme six

The method for preparing the compound shown in the general formula (Va) or the salt thereof, or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

subjecting a compound of formula (VaA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to a ring closure reaction with ammonium acetate to obtain a compound of formula (Va), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Scheme seven

The preparation method of the compound shown in the general formula (IIIaa), (IVaa) or (Vaa) or the salt thereof, or the preparation method of the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof, comprises the following steps:

reacting a compound of formula (IIIa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a halogenating agent to obtain a compound of formula (IIIaa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R is^xIs halogen;

R¹-R³、R⁵q and m are as defined in formula (IIIa).

Or a compound of formula (IVa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a halogenating agent to give a compound of formula (IVaa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R is^xIs halogen;

R¹-R³、R¹⁰-R¹²q, w, u and m are as defined in formula (IVa).

Or a compound of formula (Va) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a halogenating agent to give a compound of formula (Vaa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R is^xIs halogen;

ring B, R¹-R³、R¹⁰-R¹²Q, w, u, j and m are as defined in formula (Va).

Scheme eight

A process for the preparation of a compound of the general formula (IIIab), (iva) or (Vab) or a salt thereof, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

carrying out Suzuki coupling reaction on the compound of the general formula (IIIaa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (IIIC) in the presence of a catalyst under basic conditions to obtain the compound of the general formula (IIIab) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or a mixture thereof or the pharmaceutically acceptable salt thereof,

wherein

R^xIs halogen;

y is selected from

R^wIs a hydrogen atom or an alkyl group;

R¹-R³、R⁵、R⁷、R⁸q, s and m are as defined in formula (IIIa).

Or a compound of the general formula (IVaa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and a compound of the general formula (IVC) are subjected to a Suzuki coupling reaction in the presence of a catalyst under basic conditions to obtain the compound of the general formula (IVab) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof,

wherein

R^xIs halogen;

y is selected from

R^wIs a hydrogen atom or an alkyl group;

R¹-R³、R⁷、R⁸、R¹⁰-R¹²q, s, w, u and m are as defined in formula (IVa).

Or a compound of the general formula (Vaa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and a compound of the general formula (VC) are subjected to a Suzuki coupling reaction in the presence of a catalyst and under basic conditions to obtain a compound of the general formula (Vab) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof,

wherein

R^xIs halogen;

y is selected from

R^wIs a hydrogen atom or an alkyl group;

ring B, R¹-R³、R⁷、R⁸、R¹⁰-R¹²Q, s, w, u, j and m are as defined in formula (Va).

In the above reaction, the halogenating agent includes, but is not limited to, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, Br₂、Cl₂And I₂。

In the above reaction, the catalyst comprises a metal palladium complex catalyst or a combination of a palladium-containing catalyst and a ligand. The metal palladium complex catalyst includes, but is not limited to, tetrakistriphenylphosphine palladium, bis (dibenzylideneacetone) palladium, chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2' -amino-1, 1' -biphenyl) ] palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, 1' -bis (dibenzylidenphosphacidopadium) dichloropalladium or tris (dibenzylideneacetone) dipalladium, preferably [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium. The palladium-containing catalyst includes but is not limited to palladium/carbon, palladium dichloride, palladium acetate, preferably palladium acetate; the ligand includes but is not limited to triphenyl phosphine, tricyclohexyl phosphine, tri-n-butyl phosphine, trimethoxy phosphine and the like; preferably tricyclohexylphosphorus.

In the above reaction, the base includes organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; potassium phosphate or potassium carbonate is preferred.

The above reaction is preferably carried out in a solvent including, but 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, N-dimethylacetamide or N, N-dimethylformamide, and a mixture thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shifts (d) are given in units of 10-6 (ppm). NMR was measured using a Bruker AVANCE NEO 500M NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) and Tetramethylsilane (TMS) as an internal standard.

MS was measured using an 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), THERMO Ultratate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The average kinase inhibition and the IC50 value were measured using a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

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

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the n-hexane/ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

3- (6, 8-dihydro-5H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 1

First step of

6-fluoro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid hydrazide 5, 5-dioxide 1b

Compound 1a (300mg, 0.655mmol, prepared by the method disclosed in the patent application "CN 102695710B, intermediate S81" on page 204 of the specification) was dissolved in 6mL of acetonitrile, 1-hydroxybenzotriazole (120mg, 0.788mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (150mg, 0.782mmol) were added, the reaction was stirred at room temperature for 1 hour, hydrazine hydrate (40mg, 0.783mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title product 1b (60mg, yield: 19.4%).

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

Second step of

Compound 1b (60mg, 0.127mmol) was dissolved in 5mL of dimethyl sulfoxide, 1c (20mg, 0.173mmol, prepared by the method disclosed in example 13 on page 32 of the specification in patent application "CN 103467481A") was added, and the reaction was stirred at 100 ℃ for 48 hours. The reaction solution was cooled to room temperature, water was added thereto, extraction was performed with ethyl acetate (30mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated to obtain a crude product. The resulting residue was purified by thin layer chromatography with developer system A to give the title product 1(28mg, yield: 41.0%). MS M/z (ESI) 537.0[ M + H ];

¹H NMR(500MHz,CDCl₃)δ7.95(d,2H),7.58(d,2H),7.42m,1H),7.22(m,1H),6.75(d,1H),5.17(s,2H),4.98(s,2H),4.53(t,2H),4.36–4.22(m,4H),4.14(t,2H),4.05–3.95(m,2H),3.42(d,2H),3.00(t,2H).

example 2

3- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 2

First step of

(6-fluoro-1- (4- (morpholinomethyl) phenyl) -5, 5-dioxide-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) (3- (hydroxymethyl) morpholine) methanone 2b

The compound 6-fluoro-1- (4- (morpholinomethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 2a (1.09g, 1.31mmol, prepared by the method disclosed in the patent application "CN 102695710B", intermediate S81, page 204, the specification of which is incorporated herein by reference), 3-hydroxymethylmorpholine (200mg, 1.70mmol, Shaosuan) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (600mg,1.57mmol) were dissolved in 20mL of N, N-dimethylformamide, N, N-diisopropylethylamine (510mg,3.94mmol,0.7mL) was added and the reaction was stirred for 2 hours. The reaction was quenched by the addition of 50mL of water, the aqueous phase was extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride (50 mL. times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and purification of the residue using CombiFlash flash prep with eluent system a gave the title compound 2b (262mg, 35.9% yield).

Second step of

4- (6-fluoro-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxide-1, 4-dihydrothiochromene [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 2c

Compound 2b (262mg, 470.7. mu. mol) was dissolved in 60mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (280mg, 660.1. mu. mol, dess-martin oxidizer) was added thereto and the reaction was stirred for 2 hours. A mixed solution of 20mL of saturated aqueous sodium bicarbonate and 5mL of saturated aqueous sodium thiosulfate was added and quenched, separated, the aqueous phase was extracted with dichloromethane (20 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to give the crude title compound 2c (380mg, yield: 145%) which was used in the next reaction without purification.

The third step

The crude compound 2c (380mg, 685.1. mu. mol) was dissolved in 30mL of 1, 4-dioxane, ammonium acetate (520mg, 6.74mmol) was added, and the mixture was heated to 85 ℃ for reaction for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography using developer A to give a crude product, which was purified by high performance liquid chromatography (Boston Phlex Prep C18, eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound 2(10mg yield: 2.7%).

MS m/z(ESI):536.0[M+1]

¹H NMR(400MHz,CDCl₃):δ7.52-7.51(m,2H),7.44-7.42(m,2H),7.36-7.33(m,1H),7.19-7.17(m,1H),6.95(s,1H),6.73(d,1H),5.11(s,2H),4.95(s,2H),4.49-4.47(m,2H),4.04-4.02(m,2H),3.78-3.77(m,4H),3.63(s,2H),2.54-2.53(m,4H)。

Example 3

3- (6, 8-dihydro-5H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (1- (2-morpholinoethyl) piperidin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 3

First step of

1- (1- (tert-Butoxycarbonyl) piperidin-3-yl) -6-fluoro-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 3b

Ethyl 1- (1- (tert-butoxycarbonyl) piperidin-3-yl) -6-fluoro-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylate 5, 5-dioxide 3a (2.75g, 5.57mmol, prepared by the method disclosed in patent application "intermediate Q15 on page 176 of the specification in CN 102695710B") was dissolved in 25mL of tetrahydrofuran, and an aqueous solution of sodium hydroxide (2.5M, 5.5mL, 0.788mmol) was added and the reaction was stirred at 60 ℃ for 3 hours. After the reaction solution is cooled to room temperature, the pH of the reaction solution is adjusted to be neutral by dilute hydrochloric acid of ketone 2M, the reaction solution is decompressed and concentrated to obtain a title product 3b (2.5g), and the product is directly subjected to the next reaction without purification.

MS m/z(ESI):466.1[M+1]。

Second step of

3- (6-fluoro-3-hydrazinecarbonyl) -5, 5-thiochromeno [4,3-c ] pyrazol-1 (4H) -yl) piperidine-1-carboxylic acid tert-butyl ester 3c

Crude compound 3b (2.5g, 5.37mmol) was dissolved in 25mL acetonitrile, 1-hydroxybenzotriazole (800mg, 5.92mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (1.2g, 6.25mmol) were added, the reaction was stirred at room temperature for 1 hour, hydrazine hydrate (40mg, 0.783mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, column chromatography was performed with stirring, and the title product 3c was purified by developer system A (1.03g, yield: 39.9%).

MS m/z(ESI):478.1[M-1]。

The third step

3- (3- (6, 8-dihydro-5H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -6-fluoro-5, 5-thiochromeno [4,3-c ] pyrazol-1 (4H) -yl) piperidine-1-carboxylic acid tert-butyl ester 3d

Compound 3c (925mg, 1.92mmol) was dissolved in 15mL of dimethylsulfoxide, 5-methoxy-3, 6-dihydro-2H-1, 4-oxazine 1c (400mg, 3.47mmol, prepared as disclosed in example 13 on page 32 of the specification in patent application "CN 103467481A") was added, and the reaction was stirred for 18 hours while heating to 100 ℃. The reaction solution was cooled to room temperature, water was added thereto, extraction was performed with ethyl acetate (30 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using developer system A to give the title product 3d (1.08g, yield: 100%).

MS m/z(ESI):545.1[M+1]。

The fourth step

3- (6, 8-dihydro-5H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (piperidin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 3e

Compound 3d (51mg, 0.096mmol) was dissolved in 1mL of 1, 4-dioxane solution, dioxane hydrochloride solution (4M, 0.7mL) was added, and the mixture was stirred at room temperature for 2 hours. The dry reaction was concentrated to give the crude title product (45mg) which was used in the next reaction without purification.

The fifth step

1- (1- (2-chloroethyl) piperidin-3-yl) -3- (6, 8-dihydro-5H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -6-fluoro-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 3f

Compound 3e (41mg, 0.092mmol), an aqueous solution of chloroacetaldehyde (25mg, 0.127mmol, 40%) was dissolved in 5mL of 1, 2-dichloroethane, and sodium triacetoxyborohydride (30mg, 0.141mmol) was added thereto, followed by heating to 60 ℃ and stirring for reaction for 18 hours. The reaction was quenched by the addition of 50mL of saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (50 mL. times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL. times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and purification of the residue by thin layer chromatography using eluent system A gave the title compound 3f (18mg, 38.4% yield)

MS m/z(ESI):507.1[M+1]。

The sixth step

Compound 3f (18mg, 0.035mmol), morpholine (4mg, 0.045mmol), sodium iodide (2mg, 0.013mmol) and potassium carbonate (8mg, 0.058mmol) were dissolved in 3mL acetonitrile and the reaction was stirred at 60 ℃ for 18 h. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developer system a to give title product 3(6.4mg, yield 32.2%).

MS m/z(ESI):558.1[M+1]。

¹H NMR(500MHz,CDCl₃)δ7.77(s,1H),7.48(s,1H),7.31(t,1H),5.06(s,1H),5.05-4.92(m,2H),4.80(s,1H),4.51-4.40(m,2H),4.16-4.03(m,2H),3.81-3.68(m,3H),3.34(s,1H),3.09(s,1H),2.80-2.50(m,6H),2.24-1.76(m,10H)。

Example 4

6-chloro-3- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 4

First step of

1- (4- (Morpholinylmethyl) phenyl) hydrazine-1-carboxylic acid tert-butyl ester 4b

The compound 4- (4-iodophenyl) morpholine 4a (51g, 168.24mmol, prepared as disclosed in the patent application WO2008032191A2, page 59, example 17.1) and tert-butyl carbazate (23.347g, 176.66mmol, Shaoyuan) were dissolved in 400mL of dimethyl sulfoxide under argon, stirred for 10 minutes, added with cuprous iodide (1.603g,8.42mmol, ALDRICH), warmed to 50 ℃ and stirred for 17 hours. 400mL of water was added, the aqueous phase was extracted with ethyl acetate (300 mL. times.6), the organic phases were combined, concentrated under reduced pressure, and the residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title compound 4b (51g, 98.6% yield).

MS m/z(ESI):308.1[M+1]。

Second step of

4- (4-hydrazinobenzyl) morpholine 4c

Compound 4b (51g, 165.91mmol) was dissolved in 80mL of methanol at 0 deg.C, a1, 4-dioxane solution of hydrogen chloride (350mL, 4.0M, Germing science) was added dropwise, the temperature was naturally raised to room temperature, and the reaction was stirred for 17 hours. Concentration under reduced pressure gave the crude title compound 4c (45.4g), which was used in the next reaction without purification.

The third step

2- (8-chloro-1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 4e

The compound ethyl 2- (8-chloro-4-oxothiochroman-3-yl) -2-oxoacetate 4d (25.7g, 86.03mmol, prepared by the method disclosed in intermediate E4 on page 104 of the specification of patent application "CN 102695710B") and m-chloroperoxybenzoic acid (43.664g, 215.07mmol, Volvac) were dissolved in 250mL of dichloromethane and stirred for 17 hours. Filtration, concentration of the filtrate under reduced pressure and purification of the residue with CombiFlash flash prep with eluent system a gave the title compound 4e (28.323g, 99.5% yield).

MS m/z(ESI):330.9[M+1]。

The fourth step

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

Compound 4e (10g, 30.24mmol), compound 4c (9.192g, 33.26mmol, 75%) and acetic acid (3.632g, 60.48mmol, Hu test) were dissolved in 300mL of absolute ethanol, heated to reflux and stirred for 3 hours. 300mL of saturated sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (250 mL. times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title compound 4f (10g, 65.9% yield).

MS m/z(ESI):502.0[M+1]。

The fifth step

6-chloro-1- (4- (morpholinomethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 4g

Compound 4f (10g, 19.92mmol) was dissolved in 150mL tetrahydrofuran, and aqueous sodium hydroxide (39.8mL, 2.5M, Ready-to-use) was added and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust pH to about 3, and concentrated under reduced pressure to give 4g (17.028g, yield 180.3%) of the crude title compound, which was used in the next reaction without purification.

MS m/z(ESI):474.0[M+1]。

The sixth step

(6-chloro-1- (4- (morpholinomethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) (3- (hydroxymethyl) morpholinyl) methanone 4h

4g (952mg,2.01mmol) of the compound 3-hydroxymethylmorpholine (283mg,2.42mmol, yazashi), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (917mg,2.41mmol, Shaoyuan) and N, N-diisopropylethylamine (1.558g,12.05mmol, Adamas) were dissolved in 40mL of N, N-dimethylformamide and stirred at room temperature for 17 hours. 80mL of saturated sodium bicarbonate solution were added, the aqueous phase was extracted with ethyl acetate (80 mL. times.3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title product 4h (383mg, yield: 33.3%).

MS m/z(ESI):573.0[M+1]。

Seventh step

4- (6-chloro-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 4i

Compound 4h (333mg, 581.09. mu. mol) was dissolved in 100mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (370mg, 872.35. mu. mol, Daiss-Martin oxidizer, Adamas) was added and the reaction was stirred for 5 hours. After addition of a mixed solution of 150mL of saturated aqueous sodium bicarbonate and 1mL of saturated aqueous sodium thiosulfate, the mixture was quenched, separated, the aqueous phase was extracted with dichloromethane (80 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 4i (702mg), which was used in the next reaction without purification.

Eighth step

The crude compound 4i (702mg, 1.23mmol) was dissolved in 25mL1, 4-dioxane, ammonium acetate (948mg, 12.30mmol, Chinese medicine) was added, and the mixture was heated to 85 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified with eluent system a using CombiFlash flash prep to give a crude compound, which was purified with eluent system a to give the target compound 4(8mg yield: 1.2%).

MS m/z(ESI):552.1[M+1]。

¹H NMR(500MHz,CDCl₃):δ7.49-7.40(m,5H),7.28-7.24(m,1H),6.97-6.94(m,1H),6.89-6.85(m,1H),5.12(s,2H),4.95(s,2H),4.51-4.45(m,2H),4.07-4.00(m,2H),3.81-3.73(m,4H),3.66-3.51(m,2H),2.58-2.48(m,4H)。

Example 5

3- (1-chloro-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 5

Compound 2(30mg, 56.01. mu. mol) and N-chlorosuccinimide (23mg, 172.24. mu. mol, Shaoyuan) were dissolved in 15mL of acetonitrile, and the reaction was carried out for 24 hours at 75 ℃. To the reaction solution was added 30mL of water, the aqueous phase was extracted with ethyl acetate (30 mL. times.3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by using a Combiflash flash Rapid preparation apparatus with eluent system A to obtain the objective compound 5(4.6mg yield: 14.4%).

MS m/z(ESI):570.0[M+1]。

¹H NMR(500MHz,CDCl3):δ7.52-7.51(m,2H),7.43-7.35(m,3H),7.21-7.16(m,1H),6.73-6.72(m,1H),5.09(s,2H),4.86(s,2H),4.50-4.41(m,2H),4.05-3.97(m,2H),3.84-3.72(m,4H),3.67-3.59(m,2H),2.61-2.47(m,4H)。

Example 6

3- (1-bromo-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 6

Compound 2(30mg, 56.01. mu. mol) was dissolved in 20mL of tetrahydrofuran under argon, cooled to 0 ℃ and 1mL of a tetrahydrofuran solution of N-bromosuccinimide (20mg, 112.37. mu. mol, Shaoyuan) was added and the reaction was stirred for 1 hour. To the reaction solution was added 50mL of water, the aqueous phase was extracted with ethyl acetate (30 mL. times.3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by using a Combiflash flash Rapid preparation apparatus with eluent system A to obtain the objective compound 6(8.8mg yield: 25.6%).

MS m/z(ESI):613.9[M+1]。

¹H NMR(500MHz,CDCl₃):δ7.52-7.51(m,2H),7.43-7.41(m,2H),7.36-7.34(m,1H),7.21-7.17(m,1H),6.73-6.72(m,1H),5.10(s,2H),4.82(s,2H),4.46-4.44(m,2H),4.02-4.00(m,2H),3.78-3.76(m,4H),3.64-3.61(m,2H),2.56-2.51(m,4H)。

Example 7

6-fluoro-3- (1-methyl-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 7

Compound 6(270mg, 439.39 μmol), trimethylcyclotriboroxane tetrahydrofuran solution (331mg, 1.32mmol, 50%, nephelo), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (33mg, 45.10 μmol, enokay) and potassium carbonate (304mg, 2.20mmol, guo drug) were dissolved in 25mL of a mixed solvent of 1, 4-dioxane and water (V/V ═ 4:1) under argon atmosphere, heated to 90 ℃, and stirred for reaction for 17 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by using CombiFlash flash Rapid prep. apparatus with eluent system A to obtain target compound 7(59.1mg yield: 24.5%).

MS m/z(ESI):550.1[M+1]。

¹H NMR(500MHz,CDCl₃):δ7.51-7.49(m,2H),7.43-7.41(m,2H),7.34-7.32(m,1H),7.18-7.14(m,1H),6.74-6.72(m,1H),5.15(s,2H),4.85(s,2H),4.42-4.40(m,2H),3.99-3.97(m,2H),3.78-3.76(m,4H),3.67-3.62(m,2H),3.59-3.53(m,4H),2.18(s,3H)。

Example 8

3- (1-cyclopropyl-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 8

Compound 6(100mg, 162.73. mu. mol), cyclopropylboronic acid (42mg, 488.96. mu. mol, Shaoyuan), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (12mg, 16.40. mu. mol, Innok) and potassium phosphate (173mg, 815.01. mu. mol, Adamas) were dissolved in 20mL of 1, 4-dioxane under argon atmosphere, warmed to 90 ℃ and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by using CombiFlash flash Rapid prep. apparatus with eluent system A to obtain target compound 8(23.4mg yield: 25.0%).

MS m/z(ESI):576.0[M+1]。

¹H NMR(500MHz,CDCl₃):δ7.50-7.49(m,2H),7.42-7.40(m,2H),7.35-7.32(m,1H),7.18-7.14(m,1H),6.73-6.71(m,1H),5.09(s,2H),4.96(s,2H),4.42-4.40(m,2H),4.00-3.98(m,2H),3.80-3.77(m,4H),3.65-3.62(m,2H),2.56-2.52(m,4H),1.71-1.67(m,1H),0.93-0.87(m,4H)。

Example 9

6-fluoro-3- (6-methyl-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 9

First step of

(6-fluoro-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) (5- (hydroxymethyl) -2-methylmorpholinyl) methanone 9a

Compound 1a (915mg, 1.22mmol), (6-methylmorpholin-3-yl) methanol (160mg, 1.22mmol, prepared by the method disclosed on page 89 of the specification of the patent application "WO 2020/072377A 1"), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (696mg,1.83mmol) were dissolved in 10mL of N, N-dimethylformamide, N, N-diisopropylethylamine (788mg,6.09mmol,1.0mL) was added and the reaction stirred for 2 hours. The reaction was quenched by the addition of 50mL of water, the aqueous phase was extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride (50 mL. times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and purification of the residue using CombiFlash flash prep with eluent system a gave the title compound 9a (700mg, 100% yield).

Second step of

4- (6-fluoro-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) -6-methylmorpholine-3-carbaldehyde 9b

Compound 9a (500mg, 876.22. mu. mol) was dissolved in 60mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (557mg, 1.31mmol, dess-martin oxidizer) was added thereto and stirred at room temperature for 2 hours. A mixed solution of 20mL of saturated aqueous sodium bicarbonate and 5mL of saturated aqueous sodium thiosulfate was added and quenched, separated, the aqueous phase was extracted with dichloromethane (20 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to give the crude title compound 9b (400mg, yield: 80%) which was used in the next reaction without purification.

The third step

The crude compound 9b (400mg, 703.46. mu. mol) was dissolved in 30mL of 1, 4-dioxane, ammonium acetate (542mg, 7.03mmol) was added, and the mixture was heated to 90 ℃ for reaction for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developer a to give a crude product, which was purified by thin layer chromatography with developer system a to give the target compound 9(25mg), yield: 6.7 percent.

MS m/z(ESI):550.2[M+1]。

¹H NMR(400MHz,CDCl₃)δ7.54-7.52(m,2H),7.45-7.43(m,2H),7.35-7.34(m,1H),7.17-7.14(m,1H),6.95(s,1H),6.73-6.71(m,1H),5.16-5.06(m,3H),4.89-4.86(m,1H),4.70-4.68(m,1H),3.92-3.91(m,1H),3.87-3.84(m,1H),3.79-3.78(m,4H),3.64(s,2H),2.56-2.53(m,4H),1.41-1.40(m,3H)。

Examples 9-1, 9-2

(S) -6-fluoro-3- (6-methyl-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 9-1

(R) -6-fluoro-3- (6-methyl-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 9-2

Compound 9 was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IG 20 x 250mm, 5 μm; mobile phase: n-hexane: ethanol: 20: 80; flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compound (18mg, 23 mg).

Single configuration compound (shorter retention time):

chiral HPLC analysis: retention time 17.660 minutes, chiral purity: 100% (column CHIRALPAK IG150 × 4.6mm, 5 μm; mobile phase n-hexane: ethanol 20: 80, flow rate: 1.0 ml/min).

MS m/z(ESI):550.0[M+1]。

1H NMR(500MHz,CDCl3)δ7.55-7.53(m,2H),7.46-7.43(m,2H),7.36-7.33(m,1H),7.19-7.16(m,1H),6.96(s,1H),6.73-6.71(m,1H),5.16-5.07(m,3H),4.89-4.86(m,1H),4.70-4.67(m,1H),3.92-3.90(m,1H),3.87-3.82(m,1H),3.79-3.77(m,4H),3.64(s,2H),2.57-2.53(m,4H),1.41-1.39(d,3H)。

Single configuration compound (longer retention time):

chiral HPLC analysis: retention time 22.243 minutes, chiral purity: 100% (column CHIRALPAK IG150 × 4.6mm, 5 μm; mobile phase n-hexane: ethanol 20: 80, flow rate: 1.0 ml/min).

MS m/z(ESI):550.0[M+1]。

1H NMR(500MHz,CDCl3)δ7.54-7.53(m,2H),7.46-7.43(m,2H),7.35-7.32(m,1H),7.19-7.16(m,1H),6.95(s,1H),6.73-6.71(m,1H),5.16-5.06(m,3H),4.89-4.86(m,1H),4.70-4.67(m,1H),3.92-3.90(m,1H),3.87-3.82(m,1H),3.79-3.77(m,4H),3.64(s,2H),2.57-2.53(m,4H),1.41-1.39(d,3H)。

Example 10

3- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -7-methoxy-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 10

First step of

2- (7-methoxy-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 10b

The compound sodium ethoxide (19.267g, 56.62mmol, 20% purity) was charged in a 500mL single-neck flask, 300mL of a toluene solution of diethyl oxalate (6.207g, 42.47mmol) was added at 0 ℃, and 7-methoxythiochroman-4-one 10a (5.5g,28.31mmol, prepared by "Organic Letters,2020,22(3), 1155-. The reaction mixture was concentrated under reduced pressure, 400mL of water was added to the residue, dichloromethane extraction (200 mL. times.2) was performed, the aqueous phase was adjusted to pH 2 with 5M hydrochloric acid solution, ethyl acetate extraction (200 mL. times.3) was performed, the combined organic phases were washed with brine (200 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to give the crude title compound 10b (8.3g), which was directly subjected to the next reaction without purification.

Second step of

2- (7-methoxy-1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 10c

Crude compound 10b (8.3g, 28.20mmol) was dissolved in 200mL of dichloromethane, and m-chloroperoxybenzoic acid (12.166g, 70.50mmol) was added thereto, followed by stirring at room temperature for 17 hours. Filtration, concentration of the filtrate under reduced pressure and purification of the residue with CombiFlash flash prep with eluent system B gave the title compound 10c (8.8g), yield: 95.6 percent.

The third step

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

Compound 10c (8.8g, 26.96mmol) was dissolved in 200mL ethanol, 2c (6.7g, 32.32mmol) and glacial acetic acid (3.239g, 53.93mmol) were added, and the reaction was stirred at 90 ℃ for 2 h. The reaction was concentrated under reduced pressure, the residue was slurried with ethanol, filtered, and the filter cake was collected and dried under vacuum to give the title product 10d (10.2g), yield: 76.0 percent.

The fourth step

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

Compound 10d (10.2g,20.5mmol) was dissolved in 100mL tetrahydrofuran, sodium hydroxide (1.0M,102.5mL, stirred at ambient temperature for 4 h. the reaction was adjusted to pH 2 with 5.0M HCl solution and concentrated under reduced pressure to give crude title product 10e (16.3g, 58.8% purity) which was reacted in the next step without purification.

The fifth step

(3- (hydroxymethyl) morpholinyl) (7-methoxy-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) methanone 10f

The crude compound 10e (1.7g, 2.13mmol), oxalyl chloride (1.62g, 12.78mmol) and N, N-dimethylformamide (16mg, 218.9. mu. mol) were added to 50mL of dichloromethane and stirred at ordinary temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 50mL of methylene chloride and further morpholine-3-ylcarbinol hydrochloride (360mg, 2.34mmol) were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified using CombiFlash flash prep with eluent system a to give the title compound 10f (550mg), yield: 45.4 percent.

The sixth step

4- (7-methoxy-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 10g

Compound 10f (550mg, 967.22. mu. mol) was dissolved in 60mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (615mg, 1.45mmol, dess-martin oxidizer) was added thereto and stirred at room temperature for 2 hours. A mixed solution of 20mL of saturated aqueous sodium bicarbonate and 5mL of saturated aqueous sodium thiosulfate was added and quenched, the layers were separated, the aqueous layer was extracted with dichloromethane (20 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 10g (548mg) of the crude title compound which was used in the next reaction without purification.

Seventh step

10g (300mg, 529.45. mu. mol) of the crude compound was dissolved in 30mL of 1, 4-dioxane, and ammonium acetate (408mg, 5.29mmol) was added thereto, followed by heating to 90 ℃ for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developer a to give the objective compound 10(8mg), yield: 2.7 percent. MS M/z (ESI) 548.0[ M +1 ].

¹H NMR(400MHz,CDCl₃)δ7.63-7.62(m,1H),7.51-7.49(m,4H),6.95-6.89(m,3H),5.02(s,2H),4.95(s,2H),4.50-4.48(m,2H),4.04-4.02(m,2H),3.90(s,3H),3.79-3.77(m,4H),3.64-3.62(m,2H),2.56-2.52(m,4H)。

Example 11

3- (6, 8-dihydro-5H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-methyl-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 11

First step of

3- (o-tolylthio) propionic acid 11b

2-Methylphenylthiol 11a (25.0g, 201.2mmol, Shaoyuan) and potassium carbonate (41.7g, 301.9mmol, guyao) were dissolved in 200mL of N, N-dimethylformamide (guyao), stirred at 60 ℃ for 30min under nitrogen protection, cooled to room temperature, added with 3-bromopropionic acid (32.3g, 211.4mmol, Addemas), and stirred for 3 hours at 60 ℃ under nitrogen protection. 1000mL of water was added to the reaction mixture, and extraction was performed with ethyl acetate (300 mL. times.2); the aqueous phase was adjusted to pH about 3 with concentrated hydrochloric acid, extracted with ethyl acetate (400 mL. times.2), the combined organic phases washed successively with water (400 mL. times.2), saturated brine (400 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 11b (39g), yield: 98 percent.

MS m/z(ESI):195.2[M-1]。

Second step of

8-methylthiochroman-4-one 11c

11B (39g,198.6mmol) was dissolved in concentrated sulfuric acid (200mL) and stirred at 0 deg.C for 2h the reaction was poured into 1000mL of ice water, EA was extracted (300mL x 3), the organic phase was washed with saturated brine (300mLx 2), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated to give the crude product, and the residue was purified using a Combiflash flash Rapid prep to afford the title product 11c (15.5g) using eluent system B. Yield: and 43 percent.

MS m/z(ESI):178.9[M+1]。

The third step

2- (8-methyl-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 11d

Sodium ethoxide (59g,173.93mmol, Aldmas) was charged into a 500mL three-necked flask, diethyl oxalate (19g, 130.49mmol, dissolved in 100mL of toluene) and 11c (15.5g, 86.9mmol, dissolved in 100mL of toluene) were added at 0 deg.C, and reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and 400mL of water was added to the residue to conduct extraction with methylene chloride (200 mL. times.2); the aqueous phase was adjusted to pH about 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (200 mL. times.3), the organic phases were combined, washed with saturated brine (200 mL. times.2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 11d (24g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):279.0[M+1]。

The fourth step

2- (8-methyl-1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 11e

Crude compound 11d (24g, 86.23mmol) and m-chloroperoxybenzoic acid (29g, 172.5mmol, Wolka) were dissolved in 250mL of dichloromethane and stirred for 17 hours. Filtration, concentration of the filtrate under reduced pressure and purification of the residue with CombiFlash flash prep with eluent system a gave the title compound 11e (26g, 97.1% yield).

MS m/z(ESI):310.9[M+1]。

The fifth step

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

Compound 11e (15g, 49.01mmol), compound 4c (10g, 49.03mmol) and acetic acid (5.9g, 98.11mmol, Hu test) were dissolved in 300mL of anhydrous ethanol, heated to reflux and stirred for 3 hours. 300mL of saturated sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (250 mL. times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title compound 11f (20g, 86.9% yield).

MS m/z(ESI):482.0[M+1]。

The sixth step

6-methyl-1- (4- (morpholinomethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 11g

Compound 11f (14g, 29.07mmol) was dissolved in 150mL tetrahydrofuran, and aqueous sodium hydroxide (58.2mL, 2.5M, prepared by itself) was added and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust pH to about 3, and concentrated under reduced pressure to give 11g (21.2g) of the crude title compound, which was used in the next reaction without purification. MS M/z (ESI) 454.0[ M +1 ].

Seventh step

(3- (hydroxymethyl) morpholinyl) (6-methyl-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) methanone 11h

11g (3.0g, 3.96mmol), 3-hydroxymethylmorpholine (609mg, 3.96mmol, Shaoyuan) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (2.81mg,11.94mmol) were dissolved in 80mL of N, N-dimethylformamide, N, N-diisopropylethylamine (3.1g,23.83mmol) was added, and the reaction was stirred for 2 hours. The reaction was quenched with 100mL of water, the aqueous phase was extracted with ethyl acetate (80 mL. times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride (80 mL. times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and purification of the residue with CombiFlash flash prep at eluent system a gave the title compound 11h (1.2g, 54.7% yield).

MS m/z(ESI):553.1[M+1]。

Eighth step

4- (6-methyl-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 11i

Compound 11h (500mg, 904.74. mu. mol) was dissolved in 60mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (498.8mg, 1.17mmol, dess-martin oxidizer) was added thereto and the reaction was stirred for 2 hours. After quenching with a mixture of 20mL of saturated aqueous sodium bicarbonate and 5mL of saturated aqueous sodium thiosulfate, the aqueous phase was separated, extracted with dichloromethane (50 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 11i (500mg), which was used in the next reaction without purification.

The ninth step

The crude compound 11i (500mg, 908.05. mu. mol) was dissolved in 30mL of 1, 4-dioxane, ammonium acetate (699.9mg, 9.08mmol) was added, and the mixture was heated to 90 ℃ for reaction for 3 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developer A to give crude product, which was purified by CombiFlash flash Rapid prep. machine with eluent system A to give target compound 11(32mg yield: 6.63%).

MS m/z(ESI):532.0[M+1]。

¹H NMR(500MHz,DMSO-d₆):δ7.52(d,2H),7.43-7.36(m,4H),6.94(s,1H),6.76-6.74(m,1H),5.12(s,2H),4.86(s,2H),4.36(t,2H),3.98(t,2H),3.61-3.57(m,6H),2.68(s,3H),2.42(t,4H)。

Example 12

3- (6, 8-dihydro-5H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-methoxy-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 12

First step of

3- ((2-methoxyphenyl) thio) propanoic acid 12b

The compound 2-methoxythiophenol (25.0g, 178.31mmol, Shaosheng) and potassium carbonate (36.9g, 267.50mmol, guo Yao) were dissolved in 200mL of N, N-dimethylformamide (guo Yao), stirred at 60 ℃ for 30min under nitrogen protection, cooled to room temperature, added with 3-bromopropionic acid (28.6g, 187.28mmol, Addemas) and stirred for 3h at 60 ℃ under nitrogen protection. 1000mL of water was added to the reaction mixture, and extraction was performed with ethyl acetate (300 mL. times.2); the aqueous phase was adjusted to pH about 3 with concentrated hydrochloric acid, extracted with ethyl acetate (400 mL. times.2), the combined organic phases washed successively with water (400 mL. times.2), saturated brine (400 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 12b (37g), yield: 98 percent.

MS m/z(ESI):213.1[M+1]。

Second step of

8-Methoxythiochroman-4-one 12c

12B (37g,174.3mmol) was dissolved in concentrated sulfuric acid (200mL) and stirred at 0 ℃ for 2h the reaction was poured into 1000mL of ice water, extracted with ethyl acetate (300mL x 3), the organic phase was washed with saturated brine (300mL x 2), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated to give the crude product, and the residue was purified using a Combiflash flash Rapid prep to afford the title product 12c (1.74g, 4.3% yield) as eluent.

MS m/z(ESI):194.9[M+1]。

The third step

2- (8-methoxy-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 12d

Sodium ethoxide (6.10g, 17.92mmol, Aldmas) was charged in a 100mL three-necked flask, diethyl oxalate (1.97g, 13.49mmol, dissolved in 30mL of toluene) and 12c (1.74g, 8.95mmol, dissolved in 30mL of toluene) were added at 0 ℃ to react at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure, 80mL of water was added to the residue, and dichloromethane was extracted (80 mL. times.2); the aqueous phase was adjusted to pH about 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (70 mL. times.3), the organic phases were combined, washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 12d (2.6g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):295.0[M+1]。

The fourth step

2- (8-methoxy-1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 12e

Compound 12d (2.6g, 8.83mmol) and m-chloroperoxybenzoic acid (3.9g, 19.47mmol, Wolka) were dissolved in 250mL of dichloromethane and stirred for 17 hours. Filtration, concentration of the filtrate under reduced pressure and purification of the residue with CombiFlash flash prep with eluent system a gave the title compound 12e (2.8g, 97.1% yield).

MS m/z(ESI):326.9[M+1]。

The fifth step

6-methoxy-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide 12f

Compound 12e (1.3g, 3.98mmol), compound 4c (825.7mg, 3.98mmol) and acetic acid (478.4m g, 7.96mmol, Hu test) were dissolved in 60mL of anhydrous ethanol, heated to reflux and stirred for 3 hours. 60mL of saturated sodium bicarbonate solution were added, the mixture was extracted with ethyl acetate (80 mL. times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title compound 12f (1.63g, 82.2% yield).

MS m/z(ESI):498.0[M+1]。

The sixth step

6-methoxy-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 12g

Compound 12f (1.63g, 3.27mmol) was dissolved in 30mL tetrahydrofuran, and aqueous sodium hydroxide (6.5mL, 2.5M, prepared by itself) was added and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust pH to about 3, and concentrated under reduced pressure to give 12g (2.4g) of the crude title compound, which was used in the next reaction without purification. MS M/z (ESI) 470.0[ M +1 ].

Seventh step

(3- (hydroxymethyl) morpholinyl) (6-methoxy-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) methanone for 12h

12g (2.2g, 2.81mmol), 3-hydroxymethylmorpholine (453mg, 2.95mmol, Shaoyuan) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.99g,8.45mmol) were dissolved in 80mL of N, N-dimethylformamide, N, N-diisopropylethylamine (2.18g,16.86mmol) was added, and the reaction was stirred for 2 hours. The reaction was quenched with 100mL of water, the aqueous phase was extracted with ethyl acetate (80 mL. times.3), and the organic phases were combined, washed with saturated aqueous sodium chloride (80 mL. times.3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and purification of the residue with CombiFlash flash prep at eluent system a gave the title compound 12h (1.3g, 81.3% yield).

MS m/z(ESI):569.1[M+1]。

Eighth step

4- (6-methoxy-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 12i

Compound 12h (500mg, 879.29. mu. mol) was dissolved in 60mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (484.83mg, 1.14mmol, dess-martin oxidizer) was added thereto and the reaction was stirred for 2 hours. After quenching with a mixture of 20mL of saturated aqueous sodium bicarbonate and 5mL of saturated aqueous sodium thiosulfate, the aqueous phase was separated, extracted with dichloromethane (50 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to give the crude title compound 12i (500mg), which was used in the next reaction without purification.

The ninth step

The crude compound 12i (500mg, 882.41. mu. mol) was dissolved in 30mL of 1, 4-dioxane, ammonium acetate (680.2mg, 8.82mmol) was added, and the mixture was heated to 90 ℃ for reaction for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developer A to give the objective compound 12(35mg yield: 7.24%).

MS m/z(ESI):548.0[M+1]。

¹H NMR(500MHz,DMSO-d₆):δ7.52(d,2H),7.46-7.42(m,3H),7.26(d,1H),6.93(s,1H),6.44(d,1H),5.08(s,2H),4.86(s,2H),4.35(t,2H),3.97(t,2H),3.91(s,3H),3.62-3.58(m,6H),2.42(t,4H)。

Example 13

3- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6- (trifluoromethyl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 13

First step of

3- ((2- (trifluoromethyl) phenyl) thio) propanoic acid 13b

2- (trifluoromethyl) thiophenol 13a (10.4g,58.3mmol, TCI) was dissolved in N, N-dimethylformamide (60mL), potassium carbonate (16.1g,116.5mmol) was added, and stirring was carried out at 60 ℃ for 30 minutes. After cooling, bromopropionic acid (9.8g,64.3mmol) was added and stirring continued at 60 ℃ for 3 h. Cooling, pouring into water, adjusting to pH 2 with 2M hydrochloric acid, extracting three times with ethyl acetate, combining the organic phases, washing with brine, drying over sodium sulfate, concentrating under reduced pressure, and purifying the residue with CombiFlash flash prep with eluent system B to give the title compound 13B (11.0g), yield: 75.3 percent.

Second step of

8- (trifluoromethyl) thiochroman-4-one 13c

13b (11.0g,46.5mmol) was added to concentrated sulfuric acid (150mL) and stirred at room temperature for 3 hours. Pouring the reaction solution into ice water, and uniformly stirring. Filtration, washing with water, dissolution of the solid in ethyl acetate, washing with brine, drying over sodium sulfate, concentration under reduced pressure and purification of the residue with CombiFlash flash prep to give the title compound 13c (8.0g), yield: 71.8 percent.

The third step

2- (8- (trifluoromethyl) -4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 13d

The compound sodium ethoxide (23.5g,69.1mmol, 20% purity) was charged into a 500mL single-neck flask, and 200mL of a toluene solution of diethyl oxalate (7.6g,51.7mmol) was added at 0 ℃ followed by the addition of compound 13c (8.0g,34.5mmol), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, 300mL of water was added to the residue, dichloromethane extraction (100 mL. times.2) was performed, the aqueous phase was adjusted to pH 2 with 5M hydrochloric acid solution, ethyl acetate extraction (100 mL. times.3) was performed, the combined organic phases were washed with brine (200 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure to give the crude title compound 13d (9.1g), and the product was directly put into the next step without purification.

The fourth step

2- (8- (trifluoromethyl) -1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 13e

Crude 13d (9.1g, 27.2mmol) was dissolved in 150mL of dichloromethane, 3-chloroperoxybenzoic acid (11.6g, 57.2mmol) was added, and the mixture was stirred at room temperature for 17 hours. Concentration under reduced pressure and purification of the residue using CombiFlash flash prep with eluent system B gave the title compound 13e (9.8g), yield: 99.3 percent.

The fifth step

6- (trifluoromethyl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide 13f

13e (9.8g, 26.9mmol) was dissolved in 80mL ethanol, 4c (7.0g, 32.5mmol) and glacial acetic acid (20mL) were added and the reaction stirred at 80 ℃ for 2 h. Concentration under reduced pressure, slurrying with ethanol, filtration, and drying of the filter cake afforded title product 13f (8.0g), yield: 55.5 percent.

The sixth step

6- (trifluoromethyl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5,5-

Dioxide 13g

13f (8.0g, 14.9mmol) was dissolved in 100mL tetrahydrofuran, and an aqueous solution of sodium hydroxide (3M, 5.5mL) was added and stirred at room temperature for 17 hours. The reaction solution was adjusted to pH about 2 with 5.0M hydrochloric acid solution and concentrated under reduced pressure to give 13g (10.5g, 70% purity) of the crude title product, which was used in the next reaction without purification.

Seventh step

(6- (trifluoromethyl) -1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) (3- (hydroxymethyl) morpholinyl) methanone 13h

The crude compound 13g (2.8g,5.52mmol), the compound 3-hydroxymethylmorpholine hydrochloride (1.02g,6.64mmol, yagi), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (2.73g,7.18mmol, Shaoyuan) and N, N-diisopropylethylamine (3.6g,27.85mmol, Adamas) were dissolved in 20mL of N, N-dimethylformamide and stirred at room temperature for 17 hours. 80mL of saturated sodium bicarbonate solution were added, the aqueous phase was extracted with ethyl acetate (80 mL. times.3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title product 13h (2.4g, yield: 71.7%).

Eighth step

4- (6- (trifluoromethyl) -1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 13i

Compound 13h (510mg, 840.7. mu. mol) was dissolved in 100mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (714mg, 1.68mol, Das-Martin oxidizer, Adamax) was added to stir for 5 hours. A mixed solution of 150mL of a saturated aqueous sodium bicarbonate solution and 1mL of a saturated aqueous sodium thiosulfate solution was added to quench, the solution was separated, the aqueous phase was extracted with dichloromethane (80 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to give crude title compound 13i (200mg, yield: 39.4%) which was used in the next reaction without purification.

The ninth step

Crude compound 13i (200mg, 1.23mmol) was dissolved in 25mL1, 4-dioxane, ammonium acetate (948mg, 12.30mmol, pharmacia) was added, and the mixture was heated to 85 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by using CombiFlash flash prep. with eluent system a to obtain the objective compound 13(25mg yield: 5.2%).

MS m/z(ESI):586.0[M+1]。

¹H NMR(500MHz,DMSO-d₆):δ8.02(d,1H),7.75(t,1H),7.53(brs,2H),7.46(brs,2H),7.24(d,1H),6.95(s,1H),5.20(s,2H),4.88(s,2H),4.37(brs,2H),4.01(brs,2H),3.67(brs,6H),2.41(brs,4H)。

Example 14

3- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -7-chloro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 14

First step of

2- (7-chloro-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 14b

The compound sodium ethoxide (62.0g,182.2mmol, 20% purity) was charged in a 500mL single-neck flask, 300mL of a toluene solution of diethyl oxalate (19.9g,136.2mmol) was added at 0 ℃, and 7-chlorothiochroman-4-one 14a (18.0g,90.6mmol, prepared by "Organic Letters,2020,22(3), 1155-and 1159") was added thereto, followed by stirring at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, 400mL of water was added to the residue, dichloromethane extraction (200 mL. times.2) was performed, the aqueous phase was adjusted to pH 2 with 5M hydrochloric acid solution, ethyl acetate extraction (200 mL. times.3) was performed, the combined organic phases were washed with brine (200 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to give the crude title compound 14b (13.7g), which was directly used in the next reaction without purification.

Second step of

2- (7-chloro-1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 14c

Crude 14b (11.80g, 36.15mmol) was dissolved in 150mL of dichloromethane, 3-chloroperoxybenzoic acid (17.2g, 81.79mmol) was added, and the mixture was stirred at room temperature for 17 hours. Concentration under reduced pressure and purification of the residue using CombiFlash flash prep with eluent system B gave the title compound 14c (12.3g), yield: 98.3 percent.

The third step

7-chloro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide 14d

14c (11.3g, 33.6mmol) was dissolved in 80mL ethanol, 4c (9.0g, 43.4mmol) and glacial acetic acid (20mL) were added, and the reaction was stirred at 80 ℃ for 2 h. The reaction was cooled to room temperature, concentrated under reduced pressure, slurried with ethanol, filtered, and the filter cake dried in vacuo to give the crude title product 14d (13.9g), yield: 83.2%, the product was directly subjected to the next reaction without purification.

The fourth step

7-chloro-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 14e

Crude 14d (13.9g, 28.3mmol) was dissolved in 100mL tetrahydrofuran, and aqueous sodium hydroxide (3M, 5.5mL) was added and stirred at room temperature for 16 h. The reaction was adjusted to pH 2 with 5.0M hydrochloric acid solution and concentrated under reduced pressure to give the title product 14e (16.1g, 70% purity) which was used in the next reaction without purification.

The fifth step

(7-chloro-1- (4- (morpholinomethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) (3- (hydroxymethyl) morpholinyl) methanone 14f

Crude compound 14e (2.5g,5.12mmol), compound 3-hydroxymethylmorpholine hydrochloride (1.02g,6.64mmol, yagi), N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (2.73g,7.18mmol, yaomari) and N, N-diisopropylethylamine (3.6g,27.85mmol, adalimus) were dissolved in 20mL of N, N-dimethylformamide and stirred at room temperature for 17 hours. 80mL of saturated sodium bicarbonate solution were added, the aqueous phase was extracted with ethyl acetate (80 mL. times.3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title product 14f (2.2g, yield: 71.2%).

The sixth step

4- (7-chloro-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 14g

Compound 14f (500mg, 840.7. mu. mol) was dissolved in 100mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (714mg, 1.68mol, Das-Martin oxidizer, Adamax) was added to stir for 5 hours. A mixed solution of 150mL of a saturated aqueous sodium bicarbonate solution and 1mL of a saturated aqueous sodium thiosulfate solution was added to quench, the solution was separated, the aqueous phase was extracted with dichloromethane (80 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to obtain 14g (200mg, yield: 39.9%) of the crude title compound, which was used in the next reaction without purification.

Seventh step

14g (200mg, 1.23mmol) of the crude compound was dissolved in 25mL1, 4-dioxane, and ammonium acetate (932mg, 12.05mmol, Wako pure chemical industries, Ltd.) was added thereto and the mixture was heated to 85 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by using CombiFlash flash prep. with eluent system a to obtain the objective compound 14(26mg yield: 5.2%).

MS m/z(ESI):552.2[M+1]。

¹H NMR(500MHz,DMSO-d₆):δ8.01(s,1H),7.74(d,1H),7.55-7.52(m,4H),6.96(s,1H),6.92(d,1H),5.15(s,2H),4.92(s,2H),4.35(s,2H),3.98(s,2H),3.62(brs,6H),2.47(brs,4H)。

Example 15

3- (6, 8-dihydro-5H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -7-methyl-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 15

First step of

3- (m-tolylthio) propionic acid 15b

3-Methylthiophenol 15a (10g, 80.5mmol, Hadamard) was dissolved in 100mL of N, N-dimethylformamide, potassium carbonate (16g, 115.7mmol) was added, 3-bromopropionic acid was added with stirring at room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with 500mL of water, separated, the aqueous phase extracted with ethyl acetate (80 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude title compound 15b (8.94g, yield: 56.5%) which was used in the next reaction without purification.

MS m/z(ESI):195.0[M-1]。

Second step of

7-methylthiochroman-4-one 15c

Compound 15b (8.94g, 45.5mmol) was dissolved in 100mL of concentrated sulfuric acid and stirred at room temperature for 3 hours. The reaction solution was quenched by carefully pouring into 500g of ice water, separated, the aqueous phase was extracted with ethyl acetate (80 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using developer system B to give the title compound 15c (5.17g, yield: 63.7%).

¹H NMR(500MHz,CDCl₃)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)。

The third step

2- (7-methyl-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 15e

A single neck flask was charged with an ethanolic solution of sodium ethoxide (20g, 58.78mmol, 20%), cooled in an ice bath, diethyl oxalate (4.5g, 30.79mmol, dissolved in 50mL of toluene) was added, compound 15c (5.17g, 29.00mmol, dissolved in 50mL of toluene) was added with stirring, and stirred at room temperature for 18 h. The reaction solution was concentrated, 200mL of water was added to quench the reaction, the pH was adjusted to neutral with 3M saline solution, the aqueous phase was extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 15e (7.87g, yield: 97.5%).

MS m/z(ESI):279.0[M+1]。

The fourth step

2- (7-methyl-1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 15f

Compound 15e (7.78g, 28.28mmol) was dissolved in 240mL of dichloromethane, m-chloroperoxybenzoic acid (14g, 68.96mmol) was added in portions with ice-bath cooling, and the mixture was stirred at room temperature for 3 hours. Insoluble materials were filtered off, the filtrate was concentrated, and the residue was purified by column chromatography using system A to give the title product 15f (6.88g, yield 78.2%).

MS m/z(ESI):310.9[M+1]。

The fifth step

7-methyl-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide 15g

Compound 15f (6.88g, 22.17mmol) and intermediate 4c (4.5g, 21.71mmol) were dissolved in 150mL of ethanol, acetic acid (2.5g, 41.63mmol) was added, and the mixture was stirred under reflux for 6 hours. After the reaction was cooled to room temperature, the solid was filtered off and dried in vacuo to give 15g (14.7g) of the crude title product which was carried on to the next reaction without purification.

MS m/z(ESI):482.2[M+1]。

The sixth step

7-methyl-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 15h

15g (5g, 10.38mmol) of the crude compound was dissolved in 60mL of tetrahydrofuran, and an aqueous solution of sodium hydroxide (2.5M, 10mL) was added thereto, followed by stirring at 60 ℃ for 1 hour. After the reaction was cooled to room temperature, the pH was adjusted to neutral with 3M hydrochloric acid, the organic solution was concentrated off, and the remaining aqueous phase was lyophilized to give the crude title product 15h (9g) which was directly subjected to the next reaction without purification.

MS m/z(ESI):452.1[M-1]。

Seventh step

7-methyl-1- (4- (morpholinylmethyl) phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl chloride 5, 5-dioxide 15i

The crude compound was dissolved in 30mL of dichloromethane for 15h (2.5g, 2.75mmol, 50%), oxalyl chloride (1.7g, 13.39mmol) and a catalytic amount of N, N-dimethylformamide were added at room temperature, the reaction was stirred at room temperature for 1h and then the dry reaction was concentrated under reduced pressure to give the crude title product 15i (1.3g) which was directly reacted in the next step without purification.

Eighth step

(3- (hydroxymethyl) morpholinyl) (7-methyl-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) methanone 15j

Compound 3-hydroxymethylmorpholine hydrochloride (450mg, 2.93mmol) was dissolved in 15mL of dichloromethane, triethylamine (1.4g, 13.84mmol) was added, and the crude compound 15i (1.3g, 2.75mmol) was added under ice cooling and stirred at room temperature for 1 hour. To the reaction solution was added 200mL of water, followed by extraction with methylene chloride (80 mL. times.3), and the organic phases were combined and washed with a saturated sodium chloride solution (50 mL. times.2). Dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 15j (905mg, yield: 59.4%).

MS m/z(ESI):553.1[M+1]。

The ninth step

4- (7-methyl-1- (4- (morpholinylmethyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 15k

Compound 15j (905mg, 1.64mmol) was dissolved in 10mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (1g, 2.35mmol, dess-martin oxidant) was added under cooling in an ice bath and the reaction was stirred at room temperature for 2 hours. 20mL of saturated aqueous sodium thiosulfate solution and 100mL of water were added to quench, the layers were separated, the aqueous layer was extracted with dichloromethane (50 mL. times.3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to give the crude title compound 15k (1.09g) which was used in the next reaction without purification.

The tenth step

The crude compound 15k (1.09g, 1.98mmol) was dissolved in 10mL of 1, 4-dioxane, ammonium acetate (1.5g, 19.45mmol) was added, and the mixture was heated to 90 ℃ for reaction for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography using developer A to give a crude product, which was purified by thin layer chromatography using developer system A to give the objective compound 15(52mg yield: 4.9%).

MS m/z(ESI):532.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ7.85(s,1H),7.55(d,2H),7.49(d,2H),7.43-7.38(m,1H),6.94(s,1H),6.79(d,1H),5.10(s,2H),4.87(s,2H),4.37(t,2H),3.98(t,2H),3.62(t,4H),3.59(s,2H),2.46-2.38(m,7H)。

Example 16-1

(S) -3- (6, 8-dihydro-5H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (4- ((3-methylmorpholinyl) methyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 16-1

First step of

(S) -4- (4-iodobenzyl) -3-methylmorpholine 16c

(S) -3-methylmorpholine 16b (410mg, 4.05mmol, adamas), N, N-diisopropylethylamine (700mg, 5.42mmol) were dissolved in 10mL acetonitrile, 1- (bromomethyl) -4-iodobenzene 16a (1.2g, 4.04mmol, obtained after completion) was added at room temperature, and the mixture was stirred at room temperature for 17 hours. To the reaction mixture was added 200mL of water, followed by extraction with ethyl acetate (100 mL. times.3). The organic phases were combined, washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 16c (1.23g, yield: 95.9%).

MS m/z(ESI):317.9[M+1]。

Second step of

(S) -1- (4- ((3-methylmorpholinyl) methyl) phenyl) hydrazinecarboxylic acid tert-butyl ester 16d

16c (1.23g, 3.88mmol), tert-butyl carbazate (550mg, 4.15mmol), cuprous iodide (40mg, 210.03. mu. mol), and cesium carbonate (1.8g,5.52mmol) were placed in 10mL of dimethyl sulfoxide and heated at 50 ℃ for 18 hours under a nitrogen atmosphere. To the reaction mixture was added 300mL of water, and the mixture was extracted with ethyl acetate (100 mL. times.3). The organic phases were combined, washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 16d (1.22g, yield: 97.8%).

The third step

(S) -4- (4-hydrazinobenzyl) -3-methylmorpholine hydrochloride 16e

Compound 16d (1.22g, 3.79mmol) was dissolved in 5mL of methanol, dioxane hydrochloride (4M,8.2mL) was added, stirring was carried out at room temperature for 18 hours, and the dry reaction was concentrated to give the crude title product 16e (1.1g) which was carried on to the next step without purification.

The fourth step

(S) -6-fluoro-1- (4- ((3-methylmorpholinyl) methyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide 16f

Ethyl 2- (8-fluoro-1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetate (1.2g, 3.82mmol, prepared by the method disclosed in patent application "intermediate Q3 on page 174 of the specification in CN 102695710B") and crude compound 16e (839mg, 3.80mmol) were dissolved in 10mL of ethanol, acetic acid (450mg, 7.50mmol) was added, and the reaction was refluxed for 3 hours. The reaction solution was concentrated, 200mL of water was added to the reaction solution, the pH was adjusted to neutral with saturated aqueous sodium bicarbonate, ethyl acetate was extracted (100 mL. times.3), the organic phases were combined, washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 16f (1.388g, yield: 73.3%).

MS m/z(ESI):500.0[M+1]。

The fifth step

(S) -6-fluoro-1- (4- ((3-methylmorpholinyl) methyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 16g

Compound 16f (1.388g, 2.78mmol) was dissolved in 15mL of tetrahydrofuran solution, and an aqueous solution of sodium hydroxide (2.5M, 2.5mL) was added and the reaction was heated at 60 ℃ for 1 hour. The organic solvent was concentrated off, the residual aqueous phase was adjusted to neutral pH with 3M hydrochloric acid and the aqueous phase was lyophilized directly to give 16g (1.86g) of the crude title compound which was directly subjected to the next reaction without purification.

MS m/z(ESI):472.0[M+1]。

The sixth step

(6-fluoro-1- (4- (((S) -3-methylmorpholinyl) methyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-3-yl) (3- (hydroxymethyl) morpholinyl) methanone 16h

16g (1.70g, 1.31mmol), 3-hydroxymethylmorpholine hydrochloride (450mg, 2.90mmol, Shaoyuan) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (890mg,3.78mmol) of the crude compound were dissolved in 20mL of N, N-dimethylformamide, N, N-diisopropylethylamine (1.6g,2.94mmol,0.7mL) was added, and the reaction was stirred for 2 hours. The reaction was quenched by addition of 150mL of water, the aqueous phase was extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with a saturated aqueous solution of sodium chloride (50 mL. times.3), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography with eluent system a gave the title product 16h (1.372g, 95.2% yield).

MS m/z(ESI):571.4[M+1]。

Seventh step

4- (6-fluoro-1- (4- (((S) -3-methylmorpholinyl) methyl) phenyl) -5, 5-dioxido-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carbonyl) morpholine-3-carbaldehyde 16i

Compound 16h (1.372g, 2.40mmol) was dissolved in 15mL of dichloromethane, and (1, 1-diacetoxy-3-oxa-1, 2-benziodo-1-yl) acetate (1.5g, 3.54mmol, dess-martin's oxidizer) was added and the reaction stirred for 3 hours. A mixed solution of 100mL of saturated aqueous sodium bicarbonate and 20mL of saturated aqueous sodium thiosulfate was added and quenched, the layers were separated, the aqueous layer was extracted with dichloromethane (50 mL. times.3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to give the crude title compound 16i (1.93g, yield: 141%) which was used in the next reaction without purification.

Eighth step

Crude compound 16i (1.93g, 3.39mmol) was dissolved in 20mL of 1, 4-dioxane, ammonium acetate (2.0g, 6.74mmol) was added, and the mixture was heated to 90 ℃ for reaction for 6 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography using developer A to give a crude product, which was purified by thin layer chromatography using developer system A to give the desired compound 16-1(80mg yield: 4.3%).

MS m/z(ESI):550.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ7.63-7.51(m,3H),7.50-7.41(m,3H),6.95(s,1H),6.73-6.68(m,1H),5.24(s,2H),4.87(s,2H),4.36(t,J＝5.4Hz,2H),4.08(d,1H),3.98(t,2H),3.66(dt,2H),3.48(td,1H),3.28(d,1H),3.18(dd,1H),2.62-2.54(m,1H),2.48-2.40(m,1H),2.22-2.14(m,1H),1.04(d,3H)。

Example 16-2

(R) -3- (6, 8-dihydro-5H-imidazo [5,1-c ] [1,4] oxazin-3-yl) -6-fluoro-1- (4- ((3-methylmorpholinyl) methyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 16-2

Using the synthetic route to example 16-1, the first step starting material 16b was replaced with (R) -3-methylmorpholine to afford the title compound 16-2.

MS m/z(ESI):550.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ7.62-7.52(m,3H),7.50-7.40(m,3H),6.95(s,1H),6.71(d,1H),5.24(s,2H),4.87(s,2H),4.36(t,2H),4.08(d,1H),3.98(t,2H),3.66(dt,2H),3.48(td,1H),3.28(d,1H),3.18(dd,1H),2.57(dt,1H),2.50-2.41(m,1H),2.22-13(m,1H),1.04(d,3H)。

Example 17

3- (5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 17

First step of

2- (1, 1-dioxido-4-oxothiochroman-3-yl) -2-oxoacetic acid ethyl ester 17b

The compound ethyl 2- (4-oxothiochroman-3-yl) -2-oxoacetate 17a (1.9g, 6.456mmol, prepared by the method disclosed on page 129 of the specification in the patent application "WO 2011/058149a 1") and m-chloroperoxybenzoic acid (2.785g, 16.139mmol, wakay) were dissolved in 30mL of dichloromethane and stirred for 17 hours. Filtration, concentration of the filtrate under reduced pressure and purification of the residue with CombiFlash flash prep with eluent system a gave the title compound 17b (1.3g, 61.7% yield).

Second step of

1- (4- (Morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide 17c

Compound 17b (1.3g, 4.387mmol), compound 4c (1.0g, 4.82mmol, 75%) and acetic acid (527mg, 8.77mmol, Hu test) were dissolved in 30mL of anhydrous ethanol, heated to reflux and stirred for 3 hours. 30mL of saturated sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified using a Combiflash flash Rapid prep with eluent System A to give the title compound 17c (880mg, 42.9% yield).

MS m/z(ESI):468.0[M+1]。

The third step

1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide 17d

Compound 17c (880mg, 1.11mmol) was dissolved in 30mL of tetrahydrofuran, and aqueous sodium hydroxide (1.85mL, 3M, Ready-to-use) was added and stirred for 4 hours. Concentrated hydrochloric acid solution was added to adjust pH to about 3, and concentrated under reduced pressure to give the crude title compound 17d (827mg, 99.8% yield), which was used in the next reaction without purification.

MS m/z(ESI):440.0[M+1]。

The fourth step

1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid hydrazide 5, 5-dioxide 17e

Crude compound 17d (300mg, 0.402mmol) was dissolved in 20mL acetonitrile, 1-hydroxybenzotriazole (82mg, 0.607mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (116mg, 0.605mmol) were added, the reaction was stirred at room temperature for 1 hour, hydrazine hydrate (47mg, 0.798mmol) was further added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, column chromatography was performed with a stirring column, and the title product 17e (180mg, yield: 98.5%) was purified by developer system A.

MS m/z(ESI):454.0[M-1]。

The fifth step

Compound 17e (180mg, 0.40mmol) was dissolved in 6mL of dimethyl sulfoxide, 1c (69mg, 0.6mmol) was added, and the reaction was heated to 100 ℃ and stirred for 18 hours. The reaction solution was cooled to room temperature, water was added thereto, extraction was performed with ethyl acetate (20 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using developer system A to give the title product 17(11mg, yield: 5.3%).

MS m/z(ESI):519.1[M+1]。

¹H NMR(500MHz,CDCl₃)δ8.19-8.15(m,1H),7.58-7.54(m,3H),7.50-7.48(m,2H),7.45-7.43(m,1H),6.97-6.95(m,1H),5.09(s,2H),5.04(s,2H),4.51-4.49(m,2H),4.09-4.07(m,2H),3.79-7.77(m,4H),3.65(s,2H),2.55(m,4H)。

Example 18

3- (5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -9-methoxy-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 18

Using the synthetic route of example 17, the first step starting material 17a was replaced with ethyl 2- (5-methoxy-4-oxothiochroman-3-yl) -2-oxoacetate (prepared by replacing 11a with 3-methoxythiophenol (Bi) using the synthetic route of 11d in example 11) to afford the title compound 18(20mg yield: 10.4%).

MS m/z(ESI):549.1[M+1]。

¹H NMR(500MHz,CDCl3)δ7.80-7.78(m,1H),7.61-7.58(m,1H),7.43-7.42(m,2H),7.38-7.36(m,2H),7.05-7.04(m,1H),5.09(s,2H),4.98(s,2H),4.52-4.47(m,2H),4.09-4.05(m,2H),3.80-3.75(m,4H),3.58(s,2H),3.17(s,3H),2.53-2.49(m,4H)。

Example 19

3- (5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) -7-methoxy-1- (4- (morpholinylmethyl) phenyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide 19

Using the synthetic route of example 17, substituting the first step starting material 17a with 10b, the title compound 19 was obtained (31mg yield: 18.2%).

MS m/z(ESI):549.1[M+1]。

¹H NMR(500MHz,CDCl3)δ7.65-7.63(m,1H),7.56-7.53(m,2H),7.49-7.47(m,2H),6.93-6.86(m,2H),5.08(s,2H),5.02(s,2H),4.52-4.47(m,2H),4.09-4.05(m,2H),3.92(s,3H),3.80-3.75(m,4H),3.64(m,2H),2.56-2.53(m,4H)。

Test example:

biological evaluation

Test example 1 test for the inhibitory activity and selectivity of the compounds of the present disclosure against the PI3K delta enzyme

Firstly, the purpose of experiment is as follows:

the purpose of this experiment was to test the inhibitory effect and selectivity of compounds on the enzymatic activity of PI3K δ, according to IC₅₀Size compounds were evaluated for in vitro activity.

II, experimental principle:

ADP-Glo was used for this experiment^TMThe enzyme action of the Kinase Assay Kit, substrate is phosphorylated and ADP is generated, ADP-Glo Reagent is added to remove unreacted ATP in the reaction system, and the ADP generated by the reaction is detected by a Kinase detection Reagent (Kinase detection Reagent). By measuring the signal value in the presence of a compoundInhibition of the compound.

Third, Experimental materials

1. Instrument for measuring the position of a moving object

2. Reagent and consumable

Name of reagent	Supply company	Goods number
			PIK3CD/PIK3R1	Carna	11-103
PI103	selleckchem	S1038
			DMSO	Sigma	D8418-1L
384-well white plate	PerkinElmer	6007290

Fourth, experiment method

Test compound concentrations were 10000nM starting, 3-fold dilution, 11 concentrations, and duplicate wells. The solutions were diluted in 384-well plates in steps to 11 different concentrations of 100-fold final concentration. Transfer 50nl to compound wells of 384-well plates with Echo; 50nl of DMSO was added to each of the negative control well and the positive control well. A2-fold final Kinase solution was prepared using 1 Xkinase buffer (Kinase buffer). Add 2.5. mu.L of 2-fold final concentration kinase solution to the compound well and the positive control well, respectively; mu.L of 1 Xkinase buffer (Kinase buffer) was added to the negative control wells. The mixture was centrifuged at 1000rpm for 30 seconds, shaken and mixed, and then incubated at room temperature for 10 minutes. A2-fold final ATP concentration mixed with the substrate P1P2 was prepared using 1 Xkinase buffer (Kinase buffer). The reaction was initiated by adding 2.5. mu.L of a 2-fold final ATP and substrate mixture. The 384 well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, the reaction was carried out at room temperature for 120 minutes. 5 μ of LADP-Glo Reagent was added, centrifuged at 1000rpm for 30 seconds, shaken well and incubated at room temperature for 40 minutes. 10. mu.L of Kinase Detection Reagent (Kinase Detection Reagent) was added, centrifuged at 1000rpm for 30 seconds, shaken, mixed and incubated at room temperature for 30 minutes. The luminescence value RLU was read with an Envision microplate reader.

Fifth, data analysis

IC of compound inhibitory activity was calculated using Graphpad Prism software₅₀See table 1 below for values, results.

TABLE 1 inhibitory Activity and selectivity data (in nM) for PI3K delta enzyme for compounds of the present disclosure

The conclusion is that the compound disclosed by the invention has stronger inhibitory activity and selectivity on PI3K delta enzyme.

Claims

1. A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring a is a 5-6 membered heterocyclyl or heteroaryl;

W¹is a carbon or nitrogen atom;

R⁵selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by a group selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹、-NR⁶SO₂R⁹And R^’Is substituted with one or more substituents of (1), said R^’Selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said R^’Each independently optionally substituted by a group selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl;

R¹the same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxy, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸Cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected fromHalogen, alkyl, haloalkyl, cyano, nitro, - (CH)₂)_sNR⁷R⁸and-OR⁹Is substituted with one or more substituents of (1); when m is greater than or equal to 2, two R¹Spiro or bridged ring systems may be formed on the oxygen-containing heterocycle;

R⁴the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and- (CH)₂)_sNR⁷R⁸Is substituted with one or more substituents of (1);

m is 0, 1,2,3, 4 or 5;

n is 1 or 2;

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

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

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

t is 0, 1 or 2.

2. The compound of formula (I) according to claim 1, wherein ring a is a five-membered heteroaryl, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of the general formula (I), or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or2, which is a compound of the general formula (II), or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

R¹-R⁵m, n, q and r are as defined in claim 1.

4. A compound of general formula (I) according to any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹Is a nitrogen atom.

5. A compound of formula (I) according to claim 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹And W³Is a nitrogen atom, W²Is a carbon atom, W⁴Is a carbon atom or a nitrogen atom.

6. A compound of formula (I) according to claim 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹、W³And W⁴Is a nitrogen atom, W²Is a carbon atom; or W²Is a nitrogen atom, W¹Is a carbon atom, W³And W⁴Is a carbon atom or a nitrogen atom.

7. The compound represented by the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, which is a compound represented by the general formula (III) or (IIIa), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is¹-R³、R⁵M and q are as defined in claim 1.

8. The compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R⁵Selected from the group consisting of heterocyclyl, aryl and heteroaryl, each independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹、-NR⁶SO₂R⁹And R^’Is substituted with one or more substituents of (1), said R^’Selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said R^’Each independently optionally selected from halogen, alkyl, haloalkyl and-OR⁹Is substituted with one or more substituents of (1);

R⁶-R⁹s and t are as defined in claim 1;

preferably, R⁵Selected from aryl or heteroaryl, each independently optionally selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹、-COR⁹、-COOR⁹、-OS(O)_tR⁹、-S(O)_tR⁹、-NR⁶COR⁹、-NR⁶SO₂R⁹And R^’Is substituted with one or more substituents of (1), said R^’Selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said R^’Each independently optionally selected from halogen, alkyl, haloalkyl and-OR⁹Is substituted with one or more substituents of (1);

R⁶-R⁹s and t are as defined in claim 1.

9. The compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R⁵Selected from the group consisting of heterocyclyl, aryl and heteroaryl, each independently optionally substituted with R^’Substituted, said R^’Selected from the group consisting of cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said R^’Each independently optionally substituted with one or more substituents selected from halogen, alkyl and haloalkyl;

preferably, R⁵Selected from aryl or heteroaryl, each independently optionally substituted by R^’Substituted, said R^’Selected from the group consisting of cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said R^’Each independently optionally substituted with one or more substituents selected from halogen, alkyl and haloalkyl.

10. The compound of the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, which is a compound of the general formula (IV) or (IVa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

R¹²the same or different, each independentlySelected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH)₂)_sNR⁷R⁸、-OR⁹Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl; when u is 2 or more, two R¹²Spiro or bridged ring systems can be formed on the morpholine ring;

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

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

R¹-R³、R⁷-R⁹s, m and q are as defined in claim 1.

11. The compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group.

13. The compound of general formula (I) according to any one of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is³The same or different, each independently selected from hydrogen, halogen, halogenated C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6An alkyl group;

preferably, R³Are the same or different and are each independently selected from hydrogen, halogen and C_1-6An alkyl group.

14. The compound of formula (I) according to any one of claims 1 to 6,8, 9, 11 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁴Selected from hydrogen, halogen, C_1-6Alkyl and C_3-8A cycloalkyl group; hydrogen is preferred.

15. The compound of general formula (I) according to any one of claims 10 to 14, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹⁰Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group.

16. The compound of general formula (I) according to any one of claims 10 to 15, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹¹Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group.

17. The compound of general formula (I) according to any one of claims 10 to 16, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹²Are the same or different and are each independently hydrogen, halogen and C_1-6An alkyl group.

18. A compound of general formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17, selected from the following compounds:

19. a compound of formula (IIIA) or (IIIaA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is¹-R³、R⁵M and q are as defined in claim 7.

20. The compound of formula (IIIA) or (IIIaA) according to claim 19, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

21. a process for the preparation of a compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein L is a leaving group, preferably alkoxy, more preferably methoxy;

R¹-R³、R⁵q and m are as defined in claim 7.

22. A process for preparing a compound of formula (IIIa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein R is¹-R³、R⁵Q and m are as defined in claim 7.

23. A process for the preparation of a compound of formula (IIIaa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein R is^xIs halogen;

R¹-R³、R⁵q and m are as defined in claim 7.

24. A process for the preparation of a compound of formula (IIIab) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IIIaa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof and the compound of the general formula (IIIC) are subjected to a Suzuki coupling reaction in the presence of a catalyst and under basic conditions to obtain the compound of the general formula (IIIab) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or a mixture thereof or the pharmaceutically acceptable salt thereof, wherein

R^xIs halogen;

R^yselected from the group consisting of alkyl, haloalkyl, hydroxyalkyl,Cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and- (CH)₂)_sNR⁷R⁸Is substituted with one or more substituents of (1);

y is selected from

R^wIs a hydrogen atom or an alkyl group;

R¹-R³、R⁵、R⁷、R⁸q, s and m are as defined in claim 23.

25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) according to any one of claims 1 to 18, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

26. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for the preparation of a medicament for the inhibition of PI3K δ.

27. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for the preparation of a medicament for the treatment and/or prophylaxis of inflammatory diseases, autoimmune diseases, cancer and related diseases, preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gall bladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, Thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, said leukemia being preferably selected from chronic lymphocytic leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML) and hairy cell leukemia, said lymphoma being preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma and diffuse large B-cell lymphoma, said lung cancer being preferably non-small cell lung cancer or small cell lung cancer, said preferably Multiple Myeloma (MM), the autoimmune disease is preferably 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-transglutaminase, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, goodpasture's syndrome, Graves ' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, glomerulonephritis type A, immune thrombocytopenic purpura, Idiopathic Thrombocytopenic Purpura (ITP), interstitial cystitis, lupus nephritis, lupus erythematosus, Crohn's disease, autoimmune diseases, inflammatory diseases, autoimmune diseases, and the like, Membranous nephropathy, mixed connective tissue disease, hard blotch, Multiple Sclerosis (MS), myasthenia gravis, sudden sleep, neuromuscular sclerosis, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo and Wegener's granulomatosis, preferably lupus erythematosus or systemic lupus erythematosus, preferably pemphigus vulgaris, preferably hepatocellular carcinoma, preferably head and neck squamous cell carcinoma, preferably osteosarcoma or soft tissue sarcoma, preferably colorectal carcinoma preferably colon carcinoma or rectal carcinoma.