WO2022007924A1

WO2022007924A1 - Oxa-azabicyclic derivative, preparation method therefor and medical use thereof

Info

Publication number: WO2022007924A1
Application number: PCT/CN2021/105396
Authority: WO
Inventors: 陆标; 沈晓冬; 贺峰; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2020-07-09
Filing date: 2021-07-09
Publication date: 2022-01-13
Also published as: TW202214655A; CN115835863A

Abstract

The present disclosure relates to an oxa-azabicyclic derivative, a preparation method therefor, and the medical use thereof. In particular, the present disclosure relates to an oxa-azabicyclic derivative as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and the use thereof as a therapeutic agent, especially the use thereof as a PI3Kδ inhibitor and the use thereof in the preparation of a drug for treating conditions or symptoms improved by means of inhibiting PI3Kδ.

Description

Oxazabicyclic derivatives, their preparation method and their application in medicine

technical field

The present disclosure belongs to the field of medicine, and relates to an oxazabicyclic derivative represented by the general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a PI3Kδ Use of inhibitors and use in the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of PI3Kδ.

Background technique

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

PI3Kδ is mainly expressed in immune cells and hematopoietic cells, participates in BCR signaling in B cells, and controls the development and maturation of B cells in the body. When the body is stimulated by an antigen, the specific surface immunoglobulin Ig on the surface of BCR can bind to the antigen, resulting in the phosphorylation of ITAM in the intracellular segment of the CD79A/B complex. The phosphorylated ITAM can recruit and activate SYK and further activate BTK and its downstream molecule PLCγ2. Activated SYK can bind to the P85 subunit of PI3Kδ, activate PI3Kδ, and promote the generation of PIP3. The generated PIP3 can recognize the N-terminal domain of BTK and interact with it to mediate the recruitment of BTK to the membrane, thereby activating BTK-mediated B cell signaling induces the expression of numerous related genes. In addition, phosphorylated CD19 can also recruit PI3Kδ on the cell membrane, activate PI3Kδ, catalyze PIP2 to generate PIP3, activate AKT, and promote cell proliferation, migration, apoptosis and other processes (N Engl J Med, 379, 2052-2062). In addition to regulating B cell function, recent studies have reported that PI3Kδ activation promotes Treg cell development, maturation, and recruitment (Cancer Immunol Res, 2, 1080-1089). Inhibition of PI3Kδ can promote the proliferation and survival of CD8+ memory T cells (Cancer Res, 77, 4135-4145). Therefore, PI3Kδ is an ideal target for the treatment of B-cell lymphoma, and the development of selective PI3Kδ inhibitors as a drug for the treatment of hematological tumors has attracted more and more attention.

Idelalisib, the first selective inhibitor of PI3Kδ approved for marketing, was approved in 2014 for the treatment of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and small lymphocytic lymphoma tumor (SLL). Duvelisib (which acts on PI3Kδ and γ) was subsequently approved for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in 2018. Although PI3Kδ inhibitors have achieved very good results in the treatment of these hematological tumors, due to the poor selectivity of these early inhibitors for PI3K kinase, many drug-related hepatotoxicity and gastrointestinal toxicity have been seen in clinical practice. Toxic side effects. In order to further reduce the potential side effects of PI3Kδ inhibitors, in recent years, many companies have been actively developing second-generation highly selective PI3Kδ inhibitors, such as Parsaclisib, ME-401 and IOA-244. These drugs are currently respectively in different clinical stages.

IOA-24 is a second-generation PI3Kδ inhibitor developed by iOnctura (WO2011058149, WO2014121901). Compared with traditional PI3Kδ inhibitors, it is an ATP non-competitive inhibitor. inhibition is highly selective.

Considering that the side effects of the first-generation PI3Kδ inhibitors currently on the market are relatively obvious, which limits the use of this type of drugs in more patient populations, the development of second-generation highly selective PI3Kδ inhibitors in related patient populations There is a significant unmet medical need.

Related patent applications disclosed so far include WO2011058149A1, WO2015196759A1, WO2015196335A1, WO2014209980A1, WO2004069824A1 and the like.

SUMMARY OF THE INVENTION

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

in:

R ^{5 is} selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally is selected from halogen, alkyl, haloalkyl, nitro, cyano, _{_{hydroxyalkyl, - (CH 2) s NR}} 7 R 8, -OR 9, -COR 9, -COOR 9, -OS (O) t R ⁹ , -S(O) _t R ⁹ , -NR ⁶ COR ⁹ , -NR ⁶ SO ₂ R ⁹ and one or more substituents in R, wherein R is selected from cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, wherein each R is independently optionally selected from halogen, alkyl, haloalkyl , nitro, cyano, hydroxyalkyl, -(CH ₂ ) _s NR ⁷ R ⁸ , -OR ⁹ , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heterocyclyl substituted with one or more substituents in the aryl group;

R ^{1 are the} same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxy, hydroxyalkyl, -(CH ₂ ) _s NR ⁷ R ⁸ , cycloalkyl, Cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted selected from halogen, alkyl, haloalkyl, cyano, _{_{nitro, - (CH 2) s NR}} 7 R 8 and a substituted or more of -OR ⁹ is substituted by a group; when m is greater than or equal to 2, two R ¹ can form a spiro or bridged ring system on the heterocyclic ring to which it is connected;

R ² and R ^{4 are the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, aryl alkyl, heterocyclylalkyl, and heteroarylalkyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, alkyl halide group, halogen, cyano, nitro, -(CH ₂ ) _s NR ⁷ R ⁸ , -OR ⁹ , -COR ⁹ , -COOR ⁹ , -OS(O) _t R ⁹ , -S(O) _t R ⁹ , -NR ⁶ COR ⁹ and -NR ⁶ SO ₂ R ⁹ are substituted with one or more substituents;

R ^{3 is the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH ₂ ) _s NR ⁷ R ⁸ , -OR ⁹ , -COR ⁹ , -COOR ⁹ , _{^{-OS (O) t R 9,}} -S (O) t R 9, -NR 6 COR 9, -NR 6 SO 2 R 9, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from alkyl, haloalkyl, halo, cyano, _{_{nitro, - (CH 2) s NR}} 7 R ^{^{^{8, -OR 9, -COR 9,}}} -COOR 9,,, a _{^{-OS (O) t R 9 -S}} (O) t R 9 -NR 6 COR 9 , and -NR ⁶ SO ₂ R ⁹ or in substituted by a substituent;

or two adjacent R ³ together with the attached carbon atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, each of which is independently is optionally selected from the group consisting of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl One or more substituents in the base are substituted;

R ⁶ are each independently selected from hydrogen atoms, alkyl groups, cycloalkyl groups and aryl groups, wherein said alkyl groups, cycloalkyl groups and aryl groups are each independently optionally selected from alkyl groups, alkoxy groups, oxo groups substituted with one or more of the substituents in group, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

Or R ⁷ and R ⁸ form together with the nitrogen atom a heterocyclic group, a heterocyclic group optionally substituted selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{9 is} each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH ₂ ) _s NR ⁷ R ⁸ , cycloalkyl, heterocyclyl, aryl wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxy Substituted with one or more substituents of alkyl, 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;

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

t is 0, 1 or 2.

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

wherein R ¹ -R ⁵ , n, q and m are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ⁵ is aryl or heteroaryl, each independently optionally selected from halogen , alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH ₂ ) _s NR ⁷ R ⁸ , -OR ⁹ , -COR ⁹ , -COOR ⁹ , -OS(O) _t R ⁹ , - S(O) _t R ⁹ , -NR ⁶ COR ⁹ , -NR ⁶ SO ₂ R ⁹ and one or more substituents in R, wherein R is selected from cycloalkyl, heterocyclyl, aryl , heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each R is independently optionally selected from halogen, alkyl, haloalkyl, and -OR substituted by one or more of the substituents in ^9;

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

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer Constructs, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ⁵ is aryl or heteroaryl, each of which is independently optionally substituted by one or more substituted with one R selected from the group consisting of cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, each independently optionally selected from halogen, alkyl and substituted with one or more substituents in haloalkyl;

Preferably, R ⁵ is an aryl group, the aryl group is optionally substituted by a heterocyclylalkyl group, and the heterocyclylalkyl group is optionally selected from one or more selected from the group consisting of halogen, alkyl and haloalkyl substituted by a substituent;

More preferably, R ⁵ is phenyl substituted with morpholinylmethyl, even more preferably, R ⁵ is

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (I-1) and (I-2) or its tautomer, racemate, enantiomer Constructs, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ⁵ is a 6-10-membered aryl group, and the 6-10-membered aryl group is optionally surrounded by a 3-6-membered heterocycle substituted by C _1-6 alkyl group, the 3-6 membered heterocyclic C _1-6 alkyl group is optionally selected from one or more of _{halogen, C 1-6} alkyl and C _{1-6 haloalkyl} substituted by a substituent.

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

in

R ^{10 are the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH ₂ ) _s NR ⁷ R ⁸ , -OR ⁹ , cycloalkyl, Heterocyclyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy substituted with one or more substituents in -(CH ₂ ) _s NR ⁷ R ^8;

R ^{11 are the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, nitro, -(CH ₂ ) _s NR ⁷ R ^8. Cycloalkyl, cycloalkyloxy and cycloalkylalkyl;

R ^{12 are the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH ₂ ) _s NR ⁷ R ⁸ , -OR ⁹ , cycloalkyl, Cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; when u is greater than or equal to 2, two R ¹² can form a spiro or bridged ring system on the morpholine ring;

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

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

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

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

wherein R ¹ -R ⁴ , R ¹⁰ -R ¹² , q, u, w and m are as defined in general formula (II).

In some preferred embodiments of the present disclosure, a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{1 are the} same or different, each independently selected from hydrogen , alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxyalkyl, -(CH ₂ ) _s NR ⁷ R ⁸ , cycloalkyl, cycloalkylalkyl, cycloalkyloxy, wherein Said alkyl and cycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, cyano and -OR ⁹ ; when m is greater than or equal to 2, the two R ¹ can form a spiro or bridged ring system on the oxygen-containing heterocycle; wherein R ⁷ -R ⁹ and s are as in general formula (I), (I-1), (I-2), (II), ( As defined in II-1) and (II-2).

Preferably, R ^{1 are the} same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy and haloalkoxy, wherein said alkyl is optionally selected from halogen, cyano and -OR ⁹ with one or more substituents; R ⁹ wherein general formula (I), (I-1 ), (I-2), (II), (II-1) and (II-2) as defined in .

More preferably, R ^{1 are the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; further preferably hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) tautomers, racemates, pharmaceutically acceptable salts thereof, wherein R ² and R for identical or, diastereomers thereof, or a mixture of enantiomers or ⁴ or different, are each independently is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl and cycloalkylalkyl, wherein said alkyl and cycloalkyl are each independently optionally selected from alkyl, haloalkyl , halogen, cyano and -OR ⁹ is substituted with one or more substituents; wherein R ^{9 is} as general formula (I), (I-1), (I-2), (II), (II-1 ) and (II-2).

Preferably, R ² and R ^{4 are the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; more preferably, both R ² and R ⁴ are hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or a tautomer, racemate, to, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof, wherein R ³ are the same or different, are each independently selected from hydrogen , halogen, alkyl, haloalkyl, cyano, nitro, -(CH ₂ ) _s NR ⁷ R ⁸ and -OR ⁹ ; wherein R ⁷ -R ⁹ and s are as in general formula (I), (I-1) , (I-2), (II), (II-1) and (II-2).

Preferably, R ^{3 is the} same or different, each independently selected from hydrogen, halogen, halogenated C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkyl;

Further preferably, R ^{3 is the} same or different, and each is independently selected from hydrogen, halogen and C _1-6 alkyl;

Still preferably, R ^{3 is the} same or different, and each is independently selected from fluorine, chlorine, methyl, methoxy and trifluoromethyl;

More preferably, R ³ is fluoro.

In some preferred embodiments of the present disclosure, a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or a tautomer, racemate, to, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from hydrogen, alkyl and cycloalkyl wherein the 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, R ⁶ is a hydrogen atom or a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) tautomers, racemates, enantiomers, diastereomers, or mixtures thereof in the form of a pharmaceutically acceptable salt thereof, wherein the same or R ⁷ and R ⁸ or different and are each independently is selected from hydrogen atoms, alkyl groups, haloalkyl groups and cycloalkyl groups; or R ⁷ and R ⁸ together with the attached nitrogen atom form a heterocyclic group optionally selected from alkyl, alkoxy , substituted with one or more substituents in halogen, hydroxyalkyl and cycloalkyl;

Preferably, R ⁷ and R ^{8 are the} same or different, and are each independently selected from hydrogen atoms, C _1-6 alkyl and C _1-6 haloalkyl; or R ⁷ and R ⁸ together with the attached nitrogen atom form a heterocycle The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of C _1-6 alkyl, C _{1-6 alkoxy and halogen.}

In some preferred embodiments of the present disclosure, a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or a tautomer, racemate, to, diastereomers thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is independently selected from a hydrogen atom, an alkyl group, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected Substituted from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, cyano and amino;

Preferably, R ^{9 is} independently selected from hydrogen atoms, alkyl, haloalkyl and cycloalkyl; wherein said alkyl and cycloalkyl are each independently optionally selected from halogen, alkyl, alkoxy and haloalkane substituted with one or more substituents in the group.

More preferably, R ^{9 is} independently selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl and 3-6 membered cycloalkyl; wherein said C _1-6 alkyl and 3-6 membered cycloalkyl The cycloalkyl groups are each independently optionally substituted with one or more substituents _{selected from halogen, C 1-6} alkyl, C _1-6 alkoxy, and C _{1-6 haloalkyl.}

In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{10 are the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxy _{_{alkyl, - (CH 2) s NR}} 7 R 8 and -OR ^9; wherein the R ⁷ -R ⁹ and s are as formula (I) as defined above.

Preferably, R ^{10 is the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; more preferably hydrogen.

In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{11 are the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy , hydroxy, hydroxyalkyl, cyano and -(CH ₂ ) _s NR ⁷ R ⁸ ; wherein R ⁷ -R ⁸ and s are as defined in general formulae (II), (II-1) and (II-2) .

Preferably, R ^{11 are the} same or different and are each independently selected from hydrogen, halogen and C _1-6 alkyl; more preferably hydrogen.

In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) and (II-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{12 are the} same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxy _{_{alkyl, - (CH 2) s NR}} 7 R 8 and -OR ^9; wherein R ⁷ -R ⁹ and s are as formula (II), (II-1 ) and (II-2) as defined above.

Preferably, R ^{12 are the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; more preferably hydrogen or methyl; further preferably hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (I-1), (I-2), (II), (II-1) and (II-2) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2, preferably 0.

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

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

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

In some preferred embodiments of the present disclosure, a compound represented by general formula (II), (II-1) or (II-2) or its tautomer, racemate, enantiomer isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{1 are the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; m is 0, 1 or 2; R ² and R ^{4 are the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; R ^{3 is the} same or different, each independently selected from hydrogen, halogen, halogenated C _1-6 alkyl , C _1-6 alkoxy and C _1-6 alkyl; q is 0, 1, 2 or 3; R ^{10 is the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; w is 0, 1 or 2; R ^{11 is the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; R ^{12 is the} same or different, each independently selected from hydrogen, halogen and C _1-6 alkyl; u is 0, 1, 2 or 3.

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

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

Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or The method of its pharmaceutically acceptable salt, the method comprises the following steps:

Compounds of general formula (IA) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or salts thereof react with general formula (IB) or salts thereof , to obtain a compound of general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof,

wherein R ¹ -R ⁵ , n, q and m are as defined in general formula (I).

Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or The method of its pharmaceutically acceptable salt, the method comprises the following steps:

Compounds of general formula (IIA) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or salts thereof react with general formula (IIB) or salts thereof , to obtain a compound of general formula (II) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof,

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of the general formulae (I), (I-1), (I-2), (II), (II- 1), (II-2) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers or their mixtures, or their pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Use of isomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting PI3Kδ .

The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms of isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in preparation for the treatment and/or prevention of PI3Kδ-mediated Use in medicine for induced diseases.

The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms of isomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in preparation for the treatment and/or prevention of inflammatory diseases , use in medicines for autoimmune diseases, cancer and related diseases; in particular, the cancer and related diseases are preferably selected from the group consisting of melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, Colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, sperm Primary cell tumor, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma , astrocytoma, glioblastoma and glioma; the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia Leukemia (CML) and hairy cell leukemia; the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), Lymphoplasma cell 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 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 spine inflammation, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behcet's disease, celiac disease, anti-glutamine Transaminases, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, pulmonary hemorrhage-nephritic syndrome, Graves disease, Guillain-Barré syndrome Syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus , lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic joints inflammation, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, Sjogren's syndrome, stiff man syndrome, temporal arteritis, ulcerative colitis, vascular inflammation, vitiligo and Wegener's granulomatosis; the lupus is preferably lupus erythematosus or systemic lupus erythematosus; the pemphigus is preferably pemphigus vulgaris, the 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 also relates to a method of inhibiting PI3Kδ, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (I-1), (I-2), (II), (II-1), ( II-2) and Table A or the compounds shown or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or Pharmaceutical compositions comprising the same.

The present disclosure also relates to a method of treating and/or preventing PI3Kδ-mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (I-1), (I-2), (II) , (II-1), (II-2) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers or mixtures 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 general formula (I), (I-1), ( I-2), (II), (II-1), (II-2) and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers Construct or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in particular, the cancer and related diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer , gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureter Tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, bone tumor, neuroblastoma, neuroblastoma, neuroendocrine cancer, brain tumor , CNS cancer, myeloma, astrocytoma, glioblastoma and glioma; the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) ), chronic myeloid leukemia (CML) and hairy cell leukemia; the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin Lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma and diffuse large B-cell lymphoma; the lung cancer is preferably non-small cell lung cancer or small Cell lung cancer; the myeloma is preferably multiple myeloma (MM); the autoimmune disease is preferably selected from asthma, rheumatoid arthritis, acute disseminated encephalomyelitis (ADEM), Addison's disease , alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigus, pemphigoid, Behcet's disease, celiac disease , anti-transglutaminase, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, pulmonary hemorrhage-nephritic syndrome, Graves' disease , Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), Idiopathic cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, Psoriasis, Psoriatic Arthritis, Polymyositis, Primary Biliary Cirrhosis, Schizophrenia, Scleroderma, Sjogren's Syndrome, Sjogren's Syndrome, Stiff Man's 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 vulgaris pemphigus, 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 represented by general formula (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or its tautomerism A isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

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

The present disclosure also relates to compounds of general formulae (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the treatment and/or prevention of PI3Kδ-mediated diseases .

The present disclosure also relates to compounds of general formulae (I), (I-1), (I-2), (II), (II-1), (II-2) and Table A or their tautomers Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of inflammatory diseases , autoimmune diseases, cancer and related diseases; the diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric oncology, 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, Neuroblastoma, Neuroendocrine Cancer, Brain Tumor, CNS Cancer, Myeloma, Astrocytoma, Glioblastoma tumor and glioma; the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia; Said lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal lymphoma 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, pulmonary hemorrhage-nephritic syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, Hidradenitis suppurativa, Kawasaki disease, alpha globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary Biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, Sjogren's syndrome, stiff man 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, and 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 PI3Kδ-mediated disease in the present disclosure is selected from inflammatory diseases, autoimmune diseases, cancer and related diseases; preferably, the cancer and related diseases are preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasal Pharyngeal cancer, stomach cancer, esophagus cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, 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, neuroblastoma, neuroendocrine cancer, Brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma; the leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia; the lymphoma is preferably selected from small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, Chikin'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), HIV Dean'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, pulmonary hemorrhage-nephritic syndrome, Graves Thomas disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, alpha nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP) , interstitial cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, malignant Anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, Sjogren's syndrome, stiff man syndrome, temporal artery inflammation, 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 Preferably it is 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 can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, 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, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.

Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The 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.

Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents 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 coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This 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 non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

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

The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug to be 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 of the patient condition, patient's behavior, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.

Glossary

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 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms (eg 1, 2, 3, 4, 5 or 6). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Alkylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from the group consisting of D atoms, halogen, alkoxy, haloalkanes one of the group consisting of: group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple substituents.

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

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

The term "alkynyl" refers to an alkyl compound having 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 of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy One or more of the substituents of yl, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably, it is 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 monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members 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 rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include

etc.; preferably

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

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. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1-4 (eg 1, 2, 3 and 4) are heterocyclic atoms; more preferably contain 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) of which 1-3 (eg 1, 2 and 3) are heteroatoms; more preferably contain 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. 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 monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl 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 other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

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

The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:

Wait.

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

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

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from halo, alkyl, alkoxy, haloalkane one of the group consisting of: group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple substituents.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g. 1, 2, 3 or 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, 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 linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :

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

The aforementioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same or two different ring atoms of the parent. Derived residues, ie "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, alkyl are as defined above.

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

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

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

The term "alkylthio" refers to alkyl-S-, 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 alkoxy 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 hydroxy 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 "thiol" refers to -SH.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO _2.

The terms "oxo" and "oxo" refer to "=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, cycloalkyl are as defined above.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, the present disclosure having the structure, except that "deuterium" or "tritium" in place of a hydrogen, fluorine or instead of fluorine-labeled with ¹⁸ F- ⁽¹⁸ F isotope), or with ¹¹ C- ¹³ C-, ¹⁴ C- or rich, Compounds in which a set of carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) in place of carbon atoms are within the scope of this disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.

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

"Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group are independently of each other substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

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

"Pharmaceutically acceptable salts" refer to salts of compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

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

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. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of the 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.

"Prodrug" means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are 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 indicated that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will appreciate, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.

Synthetic methods of compounds of the present disclosure

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

Option One

The compound represented by the general formula (I) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt preparation method , including the following steps:

Compounds of general formula (IA) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or salts thereof and general formula (IB) or salts thereof are Under basic conditions, optionally in the presence of a condensing agent, the reaction is carried out to obtain the compound of general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or in the form of a mixture or a pharmaceutically acceptable salt thereof,

wherein R ¹ -R ⁵ , n, q and m are as defined in general formula (I).

Option II

The compound represented by the general formula (II) of the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable salt preparation method , including the following steps:

Compounds of general formula (IIA) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or salts thereof and general formula (IIB) or salts thereof Under basic conditions, optionally in the presence of a condensing agent, the reaction is carried out to obtain the compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or in the form of a mixture or a pharmaceutically acceptable salt thereof,

third solution

The compounds represented by the general formulae (I-1) and (I-2) of the present disclosure or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, A method for preparing a pharmaceutically acceptable salt thereof, comprising the following steps:

The general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt is subjected to chiral resolution to obtain the general formula Compounds of (I-1) and general formula (I-2) or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable Salt;

wherein R ¹ -R ⁵ , n, q and m are as defined in general formula (I).

Option 4

The compounds represented by the general formulae (II-1) and (II-2) of the present disclosure or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, A method for preparing a pharmaceutically acceptable salt thereof, comprising the following steps:

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

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

The condensing agent described in the above reaction includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N , N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-Hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azabenzotriazole azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 2-(7-benzotriazole)-N,N,N',N'-tetrazolium Methylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or benzotriazol-1-yl-oxytripyrrolidine hexafluorophosphate base phosphorus; preferably 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU).

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

detailed description

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of ^{10<"6> (ppm).} The determination of NMR was performed with a Bruker AVANCE NEO 500M nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

The determination of MS was performed with 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) or THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.

Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

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

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

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

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

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.

There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

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

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C-30°C.

The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-fluoro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxide-1 ,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 1

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

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

6-Fluoro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5- Dioxide 1a (300 mg, 0.66 mmol, prepared by the method disclosed in Intermediate S81 on page 204 of the specification in the well-known method "CN102695710B") and 2-oxa-5-azabicyclo[4.1.0]heptane Hydrochloride 1b (98mg, 0.72mmol, Nanjing Yaoshi) was added to N,N-dimethylformamide (8mL) respectively, and N,N-diisopropylethylamine (255mg, 1.97mmol) and N,N-diisopropylethylamine (255mg, 1.97mmol) and 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (324 mg, 0.85 mmol, HATU), stirred at room temperature overnight. Add 50 mL of water, and extract three times with a mixed solvent of dichloromethane and methanol (v:v=8:1), combine the organic phases, wash with water and saturated sodium chloride solution successively, and concentrate under reduced pressure. The obtained residue is subjected to silica gel column chromatography Purification with eluent system A afforded the title compound 1 (120 mg) in 33.9% yield.

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

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.61 (brs, 1H), 7.54 (brs, 2H), 7.46-7.52 (m, 3H), 6.65-6.70 (m, 1H), 5.03-5.13 ( m, 2H), 3.54-3.89 (m, 6H), 3.61 (brs, 4H), 3.27-3.39 (m, 2H), 2.40 (brs, 4H), 0.77-0.85 (m, 2H).

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

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

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

Chiral HPLC analysis: retention time 25.63 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

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

Single configuration compound 1-1 (longer retention time):

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

Chiral HPLC analysis: retention time 31.92 minutes, chiral purity: 99.1% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

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

Example 2

(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(9-methoxy-1-(4-morpholinylmethyl)phenyl)-5,5-dioxide -1,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 2

first step

1-(4-(Morpholinylmethyl)phenyl)hydrazine-1-carboxylate tert-butyl ester 2b

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

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

second step

The hydrochloride salt of 4-(4-hydrazinobenzyl)morpholine 2c

At 0°C, compound 2b (51 g, 165.91 mmol) was dissolved in 80 mL of methanol, and a solution of hydrogen chloride in 1,4-dioxane (350 mL, 4.0 M, from Yanfeng Technology) was added dropwise, and the temperature was naturally warmed to room temperature and stirred. The reaction was carried out for 17 hours. Concentration under reduced pressure gave the crude title compound 2c as the hydrochloride salt (45.4 g), which was used in the next reaction without purification.

third step

5-Methoxythiochroman-4-one 2e

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

the fourth step

2-(5-Methoxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 2f

Sodium ethoxide (1.44 g, 4.23 mmol, 20% content) was dissolved in 20 mL of toluene, cooled to 0 °C, and a solution of diethyl oxalate (463 mg, 3.166 mmol) in 20 mL of toluene was added dropwise, and compound 2e (410 mg, 2.11 mg) was added dropwise. mmol) at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, 100 mL of water was added to the residue, and extracted with dichloromethane (50 mL). ×2) washed, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2f (900 mg), which was used in the next reaction without purification.

the fifth step

2-(5-Methoxy-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 2g

Compound 2f (900 mg, 3.058 mmol) was dissolved in 30 mL of dichloromethane, 3-chloroperoxybenzoic acid (1.2 g, 6.95 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Concentrated under reduced pressure, the residue was purified by CombiFlash with eluent system B to give the title compound 2g (550mg), yield: 55.1%

Step 6

Ethyl 9-methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5 ,5-Dioxide 2h

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

Step 7

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

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

Step 8

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

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

¹ H NMR (500MHz, CDCl ₃ ) δ 7.78-7.77 (m, 1H), 7.59-7.56 (m, 1H), 7.41-7.40 (m, 2H), 7.39-7.34 (m, 2H), 7.04-7.02 (m,1H),5.00-4.69(m,2H),4.18-4.04(m,1H),3.89-3.87(m,1H),3.80-3.64(m,7H),3.56-3.51(m,2H) ,3.50-3.49(m,1H),3.15-3.11(m,3H),2.50-2.48(m,4H),1.11-0.89(m,2H).

Example 3

(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(6-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxide-1 ,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 3

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

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

first step

2-(8-Chloro-4-oxothiochroman-3-yl)-2-oxoethyl acetate 3b

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

second step

2-(8-Chloro-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 3c

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

third step

6-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate ethyl ester 5,5 - Dioxide 3d

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

the fourth step

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

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

the fifth step

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

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

¹ H NMR (500MHz, DMSO-d ₆ )δ7.65(m,1H), 7.53-7.48(m,3H), 7.45-7.42(m,2H), 6.86-6.78(m,1H), 5.14-5.04 (m, 2H), 3.93-3.54 (m, 10H), 3.42-3.36 (m, 1H), 3.32-3.11 (m, 1H), 2.41 (brs, 4H), 0.85-0.77 (m, 2H).

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

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

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

Chiral HPLC analysis: retention time 36.29 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

¹ H NMR (500MHz, DMSO-d ₆ )δ7.65(m,1H), 7.48-7.53(m,3H), 7.42-7.45(m,2H), 6.78-6.86(m,1H), 5.04-5.14 (m,2H),3.54-3.93(m,10H),3.36-3.42(m,1H),3.11-3.32(m,1H),2.41(brs,4H),0.77-0.85(m,2H).

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

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

Chiral HPLC analysis: retention time 46.78 minutes, chiral purity: 99.1% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

¹ H NMR (500MHz, DMSO-d ₆ )δ7.65(m,1H), 7.48-7.53(m,3H), 7.42-7.45(m,2H), 6.78-6.86(m,1H), 5.04-5.14 (m, 2H), 3.54-3.93 (m, 10H), 3.36-3.42 (m, 1H), 3.11-3.32 (m, 1H), 2.41 (brs, 4H), 0.77-0.85 (m, 2H).

Example 4

(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-methoxy-1-(4-morpholinylmethyl)phenyl)-5,5-dioxide -1,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 4

first step

2-(7-Methoxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 4b

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

second step

2-(7-Methoxy-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 4c

Compound 4b (8.3 g, 28.20 mmol) was dissolved in 200 mL of dichloromethane, m-chloroperoxybenzoic acid (12.166 g, 70.50 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Filtration, concentration of the filtrate under reduced pressure, and purification of the residue on a CombiFlash with eluent system B afforded the title compound 4c (8.8 g), yield: 95.6%.

third step

7-Methoxy-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate ethyl ester 5 ,5-Dioxide 4d

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

the fourth step

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

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

the fifth step

Compound 4e ((150 mg, 319.48 μmol, 58.8%), Compound 1b (52 mg, 383.5 μmol), HATU (146 mg, 383.97 μmol) and N,N-diisopropylethylamine (206 mg, 1.59 mmol) were dissolved in 5 mL N,N-dimethylformamide, stirred at room temperature for 5 hours, added 20 mL of saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined and concentrated under reduced pressure, and the obtained residue was used CombiFlash Purification by flash prep with eluent system A afforded the title product 4 (32 mg) in 18.2% yield.

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

¹ H NMR (500MHz, DMSO-d ₆ ) δ 7.56-7.46(m, 5H), 7.18-7.15(m, 1H), 6.83-6.78(m, 1H), 5.00-4.87(m, 2H), 3.87 -3.78(m, 3H), 3.72-3.58(m, 10H), 3.38-3.36(m, 1H), 3.33-3.32(m, 1H), 2.43-2.42(m, 4H), 0.94-0.76(m, 2H).

Example 5

2-oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxide-1 ,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 5

first step

3-(o-Tolylthio)propionic acid 5b

Compound 2-methylthiophenol 5a (25.0g, 201.2mmol, Shaoyuan) and potassium carbonate (41.7g, 301.9mmol, Chinese medicine) were dissolved in 200mL N,N-dimethylformamide (Chinese medicine), nitrogen Stir at 60°C for 30 minutes under protection, cool to room temperature, add 3-bromopropionic acid (32.3 g, 211.4 mmol, Admass), and continue stirring at 60°C for 3 hours under nitrogen protection. 1000 mL of water was added to the reaction solution and extracted with ethyl acetate (300 mL×2); the pH of the aqueous phase was adjusted to about 3 with concentrated hydrochloric acid, extracted with ethyl acetate (400 mL×2), and the organic phases were combined with water (400 mL×2), saturated Washed with brine (400 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 5b (39 g), yield: 98%.

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

second step

8-Methylthiochroman-4-one 5c

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

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

third step

2-(8-Methyl-4-oxothiochroman-3-yl)-2-oxoethyl acetate 5d

Sodium ethoxide (59g, 173.93mmol, Admass) was added to a 500mL three-necked flask, diethyl oxalate (19g, 130.49mmol, dissolved in 100mL of toluene) and compound 5c (15.5g, 86.9mmol, dissolved in 0 ℃) were added. in 100 mL of toluene), and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 400 ml of water was added to the residue, and extracted with dichloromethane (200 mL×2); the aqueous phase was adjusted to pH 2 with 5M hydrochloric acid solution, extracted with ethyl acetate (200 mL×3), the organic phases were combined, and the Washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate for 15 min, filtered, and the filtrate was spin-dried to obtain the title product 5d (24 g), yield: 99.0%.

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

the fourth step

2-(8-Methyl-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 5e

Compound 5d (24 g, 86.23 mmol) and m-chloroperoxybenzoic acid (29 g, 172.5 mmol, Vokai) were dissolved in 250 mL of dichloromethane and stirred for 17 hours. Filtration, concentration of the filtrate under reduced pressure, and purification of the residue on a CombiFlash with eluent system A afforded the title compound 5e (26 g, 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-carboxylate ethyl ester 5, 5-Dioxide 5f

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

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

Step 6

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

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

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

Step 7

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

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

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.52-7.50 (m, 2H), 7.41-7.36 (m, 4H), 6.73-6.69 (m, 1H), 5.01-4.90 (m, 2H), 3.94-3.52 (m, 12H), 2.67 (s, 3H), 2.40 (t, 4H), 0.94-0.75 (m, 2H).

Example 5-1, 5-2

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

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

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

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

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

Chiral HPLC analysis: retention time 30.618 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

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

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

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

Chiral HPLC analysis: retention time 36.428 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

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

Example 6-1

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

first step

(R)-4-(4-Iodobenzyl)-3-methylmorpholine 6c

(R)-3-Methylmorpholine 6b (410 mg, 4.05 mmol, Admass), N,N-diisopropylethylamine (700 mg, 5.42 mmol) were dissolved in 10 mL of acetonitrile, and 1 -(Bromomethyl)-4-iodobenzene 6a (1.2 g, 4.04 mmol) was stirred at room temperature for 17 hours. 200 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (50 mL×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 obtain the title product 6c (1.23 g). , yield: 95.9%).

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

second step

(R)-tert-butyl 1-(4-((3-methylmorpholinyl)methyl)phenyl)hydrazinecarboxylate 6d

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

third step

(R)-4-(4-hydrazinobenzyl)-3-methylmorpholine 6e hydrochloride salt

Compound 6d (1.22 g, 3.79 mmol) was dissolved in 5 mL of methanol, dioxane hydrochloride (4M, 8.2 mL) was added, and the mixture was stirred at room temperature for 18 hours. The dry reaction solution was concentrated to give the crude title product 6e as hydrochloride (839 mg) , the product is directly put into the next step without purification.

the fourth step

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

Compound 2-(8-fluoro-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoacetate (1.2 g, 3.82 mmol) and salt of crude compound 6e were combined The acid salt (839 mg) was dissolved in 10 mL of ethanol, acetic acid (450 mg, 7.50 mmol) was added, and the reaction was heated under reflux for 3 hours. The reaction solution was concentrated, 200 mL of water was added to the reaction solution, the pH was adjusted to neutral with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated brine (50 mL×2), no Dry over aqueous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 6f (1.388 g, yield: 73.3%).

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

the fifth step

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

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

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

Step 6

The crude compound 6g (200mg, 0.30mmol), compound 1b (42mg, 0.31mmol) and HATU (170mg, 0.45mmol) were dissolved in 5mL of N,N-dimethylformamide, and then N,N-diisopropyl was added Ethylamine (120 mg, 0.93 mmol, 0.15 mL), and the reaction was stirred for 2 hours. 150 mL of water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL×3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title product 6-1 (78 mg, yield 47.5%).

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

¹ H NMR (500MHz, CDCl ₃ ) δ 7.52-7.46 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.19-7.13 (m, 1H), 6.70-6.64 (m,1H),5.06-4.83(m,2H),4.16-4.10(m,1H),4.10-3.96(m,1H),3.90-3.83(m,1H),3.81-3.55(m,6H) ,3.48-3.42(m,0.5H),3.36-3.24(m,2H),3.18-3.12(m,0.5H),2.67-2.61(m,1H),2.60-2.50(m,1H),2.32- 2.24 (m, 1H), 1.09 (d, 3H), 0.94-0.79 (m, 2H).

Example 6-2

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

Using the synthetic route of Example 6-1, substituting the first step starting material 6b with (S)-3-methylmorpholine, the title compound 6-2 was prepared.

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

¹ H NMR (500MHz, CDCl ₃ ) δ 7.53-7.45 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.19-7.13 (m, 1H), 6.70-6.62 (m,1H),5.07-4.81(m,2H),4.16-4.06(m,1H),3.89-3.83(m,1H),3.82-3.70(m,4H),3.70-3.55(m,2H) ,3.48-3.43(m,1H),3.36-3.24(m,2H),3.18-3.12(m,1H),2.64(dt,1H),2.60-2.50(m,1H),2.32-2.22(m, 1H), 1.09 (d, 3H), 0.93-0.81 (m, 2H).

Example 7

2-oxa-5-azabicyclo[4.1.0]hept-5-yl(6-methoxy-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxide- 1,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 7

first step

3-((2-Methoxyphenyl)thio)propionic acid 7b

Compound 2-methoxythiophenol 7a (25.0g, 178.31mmol, Shaoyuan) and potassium carbonate (36.9g, 267.50mmol, Chinese medicine) were dissolved in 200mL N,N-dimethylformamide (Chinese medicine), Stir for 30 molecules at 60°C under nitrogen protection, cool to room temperature, add 3-bromopropionic acid (28.6 g, 187.28 mmol, Admass), and continue stirring at 60°C for 3 hours under nitrogen protection. 1000 mL of water was added to the reaction solution and extracted with ethyl acetate (300 mL×2); the pH of the aqueous phase was adjusted to about 3 with concentrated hydrochloric acid, extracted with ethyl acetate (400 mL×2), and the organic phases were combined with water (400 mL×2), saturated Washed with brine (400 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 7b (37 g), yield: 98%.

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

second step

8-Methoxythiochroman-4-one 7c

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

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

third step

2-(8-Methoxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 7d

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

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

the fourth step

2-(8-Methoxy-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 7e

Compound 7d (2.6 g, 8.83 mmol) and m-chloroperoxybenzoic acid (3.9 g, 19.47 mmol, Vokai) were dissolved in 250 mL of dichloromethane and stirred for 17 hours. Filtration, concentration of the filtrate under reduced pressure, and purification of the residue on a CombiFlash with eluent system A afforded the title compound 7e (2.8 g, 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-carboxylate ethyl ester 5 ,5-dioxide 7f

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

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

Step 6

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

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

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

Step 7

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

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

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.53-7.39 (m, 5H), 7.25 (d, 1H), 6.40-6.36 (m, 1H), 4.92-4.82 (m, 2H), 3.91 ( s, 3H), 3.79-3.52 (m, 10H), 3.41-3.37 (m, 1H), 3.32-3.28 (m, 1H), 2.41 (s, 4H), 0.95-0.75 (m, 2H).

Example 7-1, 7-2

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

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

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

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

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

Chiral HPLC analysis: retention time 35.649 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.52-7.39 (m, 5H), 7.25 (d, 1H), 6.41-6.37 (m, 1H), 4.94-4.83 (m, 2H), 3.91 ( s, 3H), 3.80-3.52 (m, 10H), 3.41-3.37 (m, 1H), 3.32-3.28 (m, 1H), 2.41 (s, 4H), 0.93-0.75 (m, 2H).

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

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

Chiral HPLC analysis: retention time 61.556 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane/ethanol/diethylamine=80/19.98/0.02 (v/v /v)).

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.52-7.39 (m, 5H), 7.25 (d, 1H), 6.41-6.37 (m, 1H), 4.94-4.83 (m, 2H), 3.91 ( s, 3H), 3.80-3.52 (m, 10H), 3.41-3.37 (m, 1H), 3.32-3.28 (m, 1H), 2.41 (s, 4H), 0.94-0.75 (m, 2H).

Example 8

(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(1-(4-morpholinylmethyl)phenyl)-5,5-dioxy-6-(trifluoro Methyl)-1,4-dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 8

first step

3-((2-(trifluoromethyl)phenyl)thio)propionic acid 8b

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

second step

8-(Trifluoromethyl)thiochroman-4-one 8c

Compound 8b (11.0 g, 46.5 mmol) was added to concentrated sulfuric acid (150 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and stirred evenly. Filtered, washed with water, the solid was dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent body A to give the title compound 8c (8.0 g) in yield : 71.8%.

third step

2-(8-(Trifluoromethyl)-4-oxothiochroman-3-yl)-2-oxoethyl acetate 8d

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

the fourth step

2-(8-(Trifluoromethyl)-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoacetate 8e

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

the fifth step

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

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

Step 6

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

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

Step 7

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

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

¹ H NMR (500MHz, DMSO-d ₆ )δ8.01(d,1H),7.75(t,1H),7.53-7.50(m,2H),7.53-7.42(m,2H),7.27-7.17(m ,1H),5.15-5.05(m,2H),3.59-3.54(m,10H),3.43-3.39(m,1H),3.30(s,1H),2.40(brs,4H),0.88-0.78(m , 2H).

Example 9

(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-chloro-1-(4-morpholinylmethyl)phenyl)-5,5-dioxide-1 ,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 9

first step

2-(7-Chloro-4-oxothiochroman-3-yl)-2-oxoethyl acetate 9b

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

second step

2-(7-Chloro-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 9c

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

third step

7-Chloro-1-(4-(morpholinylmethyl)phenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate ethyl ester 5,5 - Dioxide 9d

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

the fourth step

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

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

the fifth step

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

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

¹ H NMR (500MHz, DMSO-d ₆ )δ8.01(d,1H), 7.73-7.71(m,1H), 7.60-7.55(m,2H), 7.51-7.49(m,2H), 6.90-6.85 (m,1H),5.08-4.97(m,2H),3.91-3.55(m,10H),3.40-3.36(m,1H),3.31-3.29(m,1H),2.42(brs,4H),0.85 -0.76(m, 2H).

Example 10

(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)(7-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxide -1,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 10

first step

3-(m-Tolylthio)propionic acid 10b

3-Methylthiophenol 10a (10g, 80.5mmol, Adamas) was dissolved in 100ml of N,N-dimethylformamide, potassium carbonate (16g, 115.7mmol) was added, and 3- Bromopropionic acid, and the reaction was stirred at room temperature for 2 hours. Add 500 ml of water to quench, separate the layers, extract the aqueous phase with ethyl acetate (80 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 10b (8.94 g, yield : 56.5%), the product was directly used in the next reaction without purification.

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

second step

7-Methylthiochroman-4-one 10c

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

¹ H NMR (500MHz, CDCl ₃ ) δ 7.86(d,1H), 7.18(d,1H), 7.04(dd,1H), 3.32-3.25(m,2H), 2.90-2.82(m,2H), 2.30 (s, 3H).

third step

2-(7-Methyl-4-oxothiochroman-3-yl)-2-oxoethyl acetate 10e

Add the ethanolic solution of sodium ethoxide (20g, 58.78mmol, content 20%) in the single-necked flask, cool in ice bath, then add diethyl oxalate (4.5g, 30.79mmol, be dissolved in 50mL toluene), add compound 10c ( 5.17 g, 29.00 mmol, dissolved in 50 mL of toluene), stirred at room temperature for 18 hours. The reaction solution was concentrated, 200 ml of water was added to quench the reaction, the pH was adjusted to neutrality with 3M saline solution, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentration gave the crude title compound 10e (7.87 g, yield: 97.5%), which was directly used in the next step without purification.

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

the fourth step

2-(7-Methyl-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 10f

Compound 10e (7.78 g, 28.28 mmol) was dissolved in 240 mL of dichloromethane, m-chloroperoxybenzoic acid (14 g, 68.96 mmol) was added in portions under ice cooling, and the mixture was stirred at room temperature for 3 hours. The insolubles were filtered off, the filtrate was concentrated, and the residue was purified by column chromatography with system A to obtain the title compound 10f (6.88 g, 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 10g

Compound 10f (6.88 g, 22.17 mmol) and intermediate 2c hydrochloride (4.5 g) were dissolved in 150 mL of ethanol, acetic acid (2.5 g, 41.63 mmol) was added, and the mixture was stirred under reflux for 6 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filter cake was collected and dried under vacuum to obtain 10 g (14.7 g) of the title product, which was directly subjected to the next reaction without purification.

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

Step 6

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

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

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

Step 7

2-oxa-5-azabicyclo[4.1.0]hept-5-yl(7-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxide-1 ,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 10

The crude compound 10h (200 mg, 0.22 mmol), compound 1b (30 mg, 0.22 mmol) and HATU (100 mg, 0.26 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and then N,N-diisopropyl was added Ethylamine (140 mg, 1.00 mmol, 0.18 mL), and the reaction was stirred for 2 hours. 150 mL of water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL×3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography with eluent system A afforded the title product 10 (25 mg, 21.5% yield).

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

¹ H NMR (500MHz, DMSO-d ₆ ) δ 7.84(s, 1H), 7.58-7.51(m, 2H), 7.47(d, 2H), 7.42-7.35(m, 1H), 6.78-6.70(m ,1H),5.00-4.83(m,2H),3.93-3.84(m,1H),3.82-3.51(m,11H),3.42-3.36(m,1H),3.29(s,1H),3.10-3.03 (m, 1H), 2.44-2.36 (m, 4H), 0.88-0.72 (m, 2H).

Example 10-1, 10-2

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

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

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

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

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

Chiral HPLC analysis: retention time 32.306 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6 mm, 5 μm; mobile phase: n-hexane/ethanol=20/80 (v/v/v)).

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

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

Chiral HPLC analysis: retention time 40.111 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150*4.6 mm, 5 μm; mobile phase: n-hexane/ethanol=20/80 (v/v/v)).

Example 11

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

first step

3-((3-Chloro-2-fluorophenyl)thio)propionic acid 11b

3-Chloro-2-fluorothiophenol 11a (8g, 49.20mmol, Wuxi Kehua) was dissolved in 100mL of N,N-dimethylformamide, potassium carbonate (8.840g, 63.96mmol) was added, 60°C After stirring for 30 minutes, 3-bromopropionic acid (8.279 g, 54.12 mmol, Adamas) was added, and the reaction was stirred at 60° C. for 2 hours. Add 500 mL of water to quench, extract with ethyl acetate (200 mL×1), adjust the pH of the aqueous phase to about 3 with concentrated hydrochloric acid, extract the aqueous phase with ethyl acetate (300 mL×3), combine the organic phases, anhydrous sodium sulfate It was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 11b (11.166 g, yield: 96.7%), which was used in the next reaction without purification.

second step

7-Chloro-8-fluorothiochroman-4-one 11c

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

third step

2-(7-Chloro-8-fluoro-4-oxothiochroman-3-yl)-2-oxoethyl acetate 11d

Add the ethanolic solution of sodium ethoxide (27.423g, 80.60mmol, 20%, TCI) and 125mL of toluene in the single-necked flask, cool in an ice bath, then add diethyl oxalate (8.834g, 60.45mmol, Shanghai test), add under stirring conditions Compound 11c (8.731 g, 40.30 mmol) was stirred at room temperature for 17 hours. The reaction solution was concentrated, 600 mL of water was added to quench the reaction, the pH was adjusted to about 3 with concentrated hydrochloric acid, the aqueous phase was extracted with ethyl acetate (250 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The crude title compound 11d was obtained (11.919 g, yield: 93.4%).

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

the fourth step

2-(7-Chloro-8-fluoro-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 11e

Compound 11d (11.919 g, 37.63 mmol) was dissolved in 130 mL of dichloromethane, m-chloroperoxybenzoic acid (19.100 g, 94.08 mmol) was added in portions under ice cooling, and the mixture was stirred at room temperature for 17 hours. The insolubles were filtered off, the filtrate was concentrated, and the residue was purified by column chromatography with system A to obtain the title compound 11e (11.5 g, yield: 87.6%).

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

the fifth step

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

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

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

Step 6

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

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

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

Step 7

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

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

¹ H NMR (500MHz, DMSO-d ₆ ) δ 7.86-7.83 (m, 1H), 7.53-7.47 (m, 4H), 6.71-6.66 (m, 1H), 5.17-5.07 (m, 2H), 4.04 -3.58(m, 11H), 2.50-2.41(m, 5H), 0.93-0.78(m, 2H).

Example 12

2-oxa-5-azabicyclo[4.1.0]hept-5-yl(9-methyl-1-(4-(morpholinylmethyl)phenyl)-5,5-dioxide-1 ,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone 12

first step

2-(5-Methyl-4-oxothiochroman-3-yl)-2-oxoethyl acetate 12a

Add the ethanolic solution of sodium ethoxide (13g, 38.21mmol, content 20%) in the single-necked flask, cool in ice bath, then add diethyl oxalate (3.0g, 20.53mmol, be dissolved in 50mL toluene), add compound 10d ( 3.38 g, 18.93 mmol, dissolved in 50 mL of toluene), stirred at room temperature for 18 hours. The reaction solution was concentrated, 200 ml of water was added to quench the reaction, the pH was adjusted to neutrality with 3M saline solution, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentration gave the crude title compound 12a (3.66 g, yield: 69.56%), which was directly used in the next reaction without purification.

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

second step

2-(5-Methyl-1,1-dioxy-4-oxothiochroman-3-yl)-2-oxoethyl acetate 12b

Compound 12a (3.66 g, 13.17 mmol) was dissolved in 50 mL of dichloromethane, m-chloroperoxybenzoic acid (6 g, 29.55 mmol, content 85%) was added in portions under ice cooling, and the mixture was stirred at room temperature for 3 hours. The insolubles were filtered off, the filtrate was concentrated, and the residue was purified by column chromatography with system A to obtain the crude title compound 12b (7.3 g, crude).

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

third step

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

Crude compound 12b (7.3 g, 12.94 mmol) and intermediate 2c hydrochloride (3.6 g) were dissolved in 50 mL of ethanol, acetic acid (1.5 g, 24.98 mmol) was added, and the mixture was stirred under reflux for 6 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filter cake was collected and dried under vacuum to obtain the title product 12c (6.8 g), which was directly subjected to the next reaction without purification.

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

the fourth step

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

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

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

the fifth step

The crude compound 12d (200 mg, 0.22 mmol), compound 1b (40 mg, 0.29 mmol) and HATU (160 mg, 0.42 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and then N,N-diisopropyl was added Ethylamine (140 mg, 1.00 mmol, 0.18 mL), and the reaction was stirred for 2 hours. 150 mL of water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL×3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography with eluent system A afforded the title product 12 (62 mg, 43.8% yield).

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

¹ H NMR (500MHz, DMSO-d ₆ )δ7.90(d,1H), 7.64(t,1H), 7.54(d,1H), 7.45(d,2H), 7.28(s,2H), 4.86( s,2H),3.84-3.48(m,10H),3.42-3.36(m,1H),3.30(s,1H),2.37(s,4H),1.62(s,3H),0.96-0.76(m, 2H).

Comparative Example A1

(2H-benzo[b][1,4]oxazin-4(3H)-yl)(6-fluoro-1-(4-(morpholinomethyl)phenyl)-5,5-dioxide- 1,4-Dihydrothiochromeno[4,3-c]pyrazol-3-yl)methanone A1

Compound 1a and 3,4-dihydro-2H-benzo[b][1,4]oxazine A1a (115 mg, 0.85 mmol, Adamas) were added to N,N-dimethylformamide (20 mL) respectively , N,N-diisopropylethylamine (423mg, 3.27mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl were added successively under stirring. Urea hexafluorophosphate (498 mg, 1.31 mmol, HATU) was stirred at room temperature overnight. Add 50 mL of water, and extract three times with a mixed solvent of dichloromethane and methanol (v:v=8:1), combine the organic phases, wash successively with water and saturated sodium chloride solution, and concentrate under reduced pressure. The obtained residue is subjected to silica gel column chromatography was purified by eluent system A to give the title compound A1 (32 mg, yield: 8.5%).

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

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.51 (d, 2H), 7.39-7.32 (m, 3H), 7.20-7.06 (m, 3H), 6.94-6.90 (m, 2H), 6.69 ( d, 1H), 4.79 (s, 2H), 4.43-4.36 (m, 4H), 3.74 (t, 4H), 3.68 (s, 2H), 2.50 (t, 4H).

Test case:

Biological evaluation

Test Example 1. Inhibitory activity and selectivity test of compounds of the present disclosure on PI3Kδ enzyme

1. The purpose of the experiment:

The purpose of this experiment is to test the inhibitory effect and selectivity of the compound on the enzymatic activity of PI3Kδ, and to evaluate the in vitro activity of the compound _{according to the IC 50 size.}

2. Experimental principle:

In this experiment, the ADP-Glo ^TM Kinase Assay Kit was used. Under the action of the enzyme, the substrate was phosphorylated and ADP was produced at the same time. ADP-Glo Reagent was added to remove the unreacted substances in the reaction system. ATP, Kinase detection reagent (Kinase detection reagent) detects the ADP produced by the reaction. The inhibition rate of the compound is calculated by measuring the signal value in the presence of the compound.

3. Experimental materials

1. Instrument

仪器名称equipment name	供货公司supply company	型号model
离心机centrifuge	EppendorfEppendorf	54305430
酶标仪Microplate reader	Perkin ElmerPerkin Elmer	Envision，SN.1050214Envision, SN.1050214
Echo 550Echo 550	LabcyteLabcyte	Echo 550Echo 550

2. Reagents and consumables

试剂名称Reagent name	供货公司supply company	货号article number
PIK3CD/PIK3R1PIK3CD/PIK3R1	CarnaCarna	11-10311-103
PI103PI103	selleckchemselleckchem	S1038S1038
DMSODMSO	SigmaSigma	D8418-1LD8418-1L
384-孔白色板384-well white plate	PerkinElmerPerkinElmer	60072906007290

Fourth, the experimental method

The test concentration of the test compound is 10000nM initial, 3-fold dilution, 11 concentrations, repeated well test. 11 different concentration solutions were serially diluted to 100-fold final concentration in 384-well plates. 50nL was transferred to compound wells of 384-well plate with Echo; 50nL of DMSO was added to negative and positive control wells, respectively. Kinase solution at 2x final concentration was prepared with 1x Kinase buffer. Add 2.5 μL of 2x final concentration of kinase solution to compound wells and positive control wells respectively; add 2.5 μL of 1× kinase buffer to negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 10 minutes. A mixed solution of 2x final concentration of ATP and substrate P1P2 was prepared in 1x kinase buffer. The reaction was initiated by adding 2.5 μL of a mixed solution of 2x final concentration of ATP and substrate. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix well, and react at room temperature for 120 minutes. Add 5 μL ADP-Glo reagent, centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 40 minutes. Add 10 μL of kinase detection reagent, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 30 minutes after shaking and mixing. The luminescence value RLU was read with an Envision microplate reader.

The structure of compound B is:

Compound B was prepared by the method disclosed in the patent "Example 339 on page 339 of the specification in CN102695710B".

5. Data Analysis

Calculated using Graphpad Prism software compound to inhibit the activity of IC ₅₀ values, see Table 1 results.

Table 1 Inhibitory and selective activity data (unit nM) of compounds of the present disclosure on PI3Kδ enzyme

Conclusion: The disclosed compounds have strong inhibitory activity and selectivity to PI3Kδ enzyme.

Test Example 2. Proliferation inhibition test of the compounds of the present disclosure on TMD-8 cells

1. The purpose of the experiment:

The purpose of this experiment is to test the inhibitory effect of the compound on the proliferation activity of TMD-8 cells, and to evaluate the in vitro activity of the compound _{according to the IC 50 size.}

2. Experimental principle:

ATP is an indicator of the metabolism of living cells.

The Luminescent Cell Viability Assay is a homogeneous assay for detecting the number of viable cells by quantifying ATP.

3. Experimental equipment, materials and reagents

laboratory apparatus:

(1) Microplate reader (BMG, PHERAstar)

Experimental Materials:

(1) 96-well plate (Corning, 3903)

(2) 96-hole U-plate (Corning, 3795)

(3)TMD-8(ETERNITY BIOSCIENCE INC.)

Experimental reagents:

(1) Fetal bovine serum (Gibco, 10099-141)

(2) RPMI 1640 medium (Hyclone, SH30809.01B)

(3)

Luminescent cell viability assay (Promege, G7573)

(4) PBS (Hyclone, SH30256.01)

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

Fourth, the experimental method:

Add 180 μL of TMD-8 cell suspension to a 96-well cell culture plate, the number is 2000 cells/well, the medium is RPMI1640 with 10% FBS, and only 200 μL of RPMI1640 with 10% FBS is added to the periphery of the 96-well plate. The plates were incubated in an incubator (37°C, 5% CO ₂ ) for 24 hours. The next day, 20 μL of the formulated compounds at different concentrations (20 μM for the initial concentration, 3-fold dilution, 9 concentrations in total) were added to the culture plate. The plates were incubated in an incubator for 6 d (37°C, 5% CO ₂ ). After 6 days, add 100 μl of the mixed Cell Titer-Glo to each well (10 mL of buffer is added to the corresponding brown bottle containing the substrate), shake and mix well, place at room temperature for 10 min, and read the chemiluminescence signal value in PHERAstar, Data were processed using GraphPad software.

5. Experimental data

The inhibitory activity of the compounds of the present disclosure on the proliferation of TMD-8 cells can be determined by the above test, and the measured IC ₅₀ values are shown in Table 2.

Table 2 discloses compounds TMD-8 cell proliferation inhibition IC ₅₀

实施例编号Example number	IC ₅₀/nM IC ₅₀ / nM	最大抑制(％)Maximum inhibition (%)
11	414414	100.96100.96
1-21-2	299.6299.6	101.2101.2
33	512.6512.6	101.5101.5
3-23-2	192.7192.7	101.4101.4
44	295.7295.7	101.4101.4
5-25-2	485485	100.8100.8
77	29.229.2	101.7101.7
1111	258.4258.4	101.4101.4
对照例A1Comparative Example A1	3208.03208.0	69.269.2

Conclusion: The disclosed compounds have good inhibitory activity on the proliferation of TMD-8 cells.

Claims

A compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof:

in:

R 5 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally is selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH 2) s NR 7 R 8, -OR 9, -COR 9, -COOR 9, -OS (O) t R 9 , -S(O) t R 9 , -NR 6 COR 9 , -NR 6 SO 2 R 9 and one or more substituents in R, wherein R is selected from cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, wherein each R is independently optionally selected from halogen, alkyl, haloalkyl , nitro, cyano, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , -OR 9 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heterocyclyl substituted with one or more substituents in the aryl group;

R 1 are the same or different, each independently selected from hydrogen, alkyl, halogen, alkoxy, haloalkoxy, cyano, hydroxy, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , cycloalkyl, Cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted selected from halogen, alkyl, haloalkyl, cyano, nitro, - (CH 2) s NR 7 R 8 and a substituted or more of -OR 9 is substituted by a group; when m is greater than or equal to 2, two R 1 can form a spiro or bridged ring system on the heterocyclic ring to which it is connected;

R 2 and R 4 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, aryl alkyl, heterocyclylalkyl, and heteroarylalkyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, alkyl halide group, halogen, cyano, nitro, -(CH 2 ) s NR 7 R 8 , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t R 9 , -S(O) t R 9 , -NR 6 COR 9 and -NR 6 SO 2 R 9 are substituted with one or more substituents;

R 3 is the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8 , -OR 9 , -COR 9 , -COOR 9 , -OS (O) t R 9, -S (O) t R 9, -NR 6 COR 9, -NR 6 SO 2 R 9, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted group selected from alkyl, haloalkyl, halo, cyano, nitro, - (CH 2) s NR 7 R 8, -OR 9, -COR 9, -COOR 9,,, a -OS (O) t R 9 -S (O) t R 9 -NR 6 COR 9 , and -NR 6 SO 2 R 9 or in substituted by a substituent;

Or two adjacent R 3 together with the attached carbon atoms form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, each of which is independently is optionally selected from the group consisting of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl One or more substituents in the base are substituted;

R 6 are each independently selected from hydrogen atoms, alkyl groups, cycloalkyl groups and aryl groups, wherein said alkyl groups, cycloalkyl groups and aryl groups are each independently optionally selected from alkyl groups, alkoxy groups, oxo groups substituted with one or more of the substituents in group, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

Or R 7 and R 8 form together with the nitrogen atom a heterocyclic group, a heterocyclic group optionally substituted selected from alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy , substituted with one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 9 is each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -(CH 2 ) s NR 7 R 8 , cycloalkyl, heterocyclyl, aryl wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxy Substituted with one or more substituents of alkyl, 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;

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

t is 0, 1 or 2.
The compound represented by the general formula (I) according to claim 1 or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or its pharmaceutically acceptable Use salts, wherein R 5 is aryl or heteroaryl, each independently optionally selected from halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, - (CH 2 ) s NR 7 R 8 , -OR 9 , -COR 9 , -COOR 9 , -OS(O) t R 9 , -S(O) t R 9 , -NR 6 COR 9 , -NR 6 SO 2 R 9 and one or more substituents in R are substituted, and said R is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aryl group and a heteroaryl group, said R is independently selected from optionally substituted with halo, alkyl, haloalkyl, -OR 9, and one or more substituents;

R 6 -R 9 , s and t are as defined in claim 1 .
The compound represented by the general formula (I) according to any one of claims 1 to 2 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R 5 is aryl or heteroaryl, each of said aryl or heteroaryl is independently optionally substituted with one or more Rs selected from cyclic Alkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, each of said R is independently optionally substituted by one or more substituents selected from halogen, alkyl and haloalkyl replace.
The compound represented by the general formula (I) according to claim 1 or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or its pharmaceutically acceptable Use salt, which is the compound represented by general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable Salt:

in

R 10 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , -OR 9 , cycloalkyl, Heterocyclyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy substituted with one or more substituents in -(CH 2 ) s NR 7 R 8;

R 11 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, nitro, -(CH 2 ) s NR 7 R 8. Cycloalkyl, cycloalkyloxy and cycloalkylalkyl;

R 12 are the same or different, each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, -(CH 2 ) s NR 7 R 8 , -OR 9 , cycloalkyl, Cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; when u is greater than or equal to 2, two R 12 can form a spiro or bridged ring system on the morpholine ring;

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

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

R 1 -R 4 , R 7 -R 9 , s, m and q are as defined in claim 1 .
The compound represented by the general formula (I) according to any one of claims 1 to 4 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R 1 are the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; preferably, R 1 is hydrogen.
The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; preferably, both R 2 and R 4 are hydrogen.
The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R 3 is the same or different, each independently selected from hydrogen, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkyl;

Preferably, R 3 is the same or different, and each is independently selected from hydrogen, halogen and C 1-6 alkyl.
The compound represented by the general formula (I) according to any one of claims 4 to 7 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R 10 is the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; preferably, R 10 is hydrogen.
The compound represented by the general formula (I) according to any one of claims 4 to 8 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R 11 is the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; preferably, R 11 is hydrogen.
The compound represented by the general formula (I) according to any one of claims 4 to 9 or its tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or diastereomer In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R 12 is the same or different, each independently selected from hydrogen, halogen and C 1-6 alkyl; preferably, R 12 is hydrogen.
The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture or a pharmaceutically acceptable salt thereof selected from:
A kind of preparation of the compound shown in the general formula (I) according to claim 1 or its tautomer, racemate, enantiomer, diastereomer or its mixture form or The method of its pharmaceutically acceptable salt, the method comprises the following steps:

A compound of general formula (IA) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof with general formula (IB) or Its pharmaceutically acceptable salts are reacted to obtain the compound of general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable form Salt,

wherein R 1 -R 5 , n, q and m are as defined in claim 1 .
A pharmaceutical composition containing a therapeutically effective amount of a compound of the general formula (I) according to any one of claims 1 to 11 or a tautomer, a racemate thereof , enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, racemate, enantiomer, diastereomer, or its Use of a mixture form, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for inhibiting PI3Kδ.
The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, racemate, enantiomer, diastereomer, or its Use of a mixture form, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 13, in the preparation of a medicament for the treatment and/or prevention of inflammatory diseases, autoimmune diseases, cancer and related diseases, in particular , the cancer and related diseases are selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, true Polycythemia, pediatric oncology, 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, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, myeloma, astrocytoma, glioblastoma and glioma, said The leukemia is preferably selected from chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia, and the lymphoma is preferably selected from small Lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B cell lymphoma and diffuse large B cell lymphoma, the lung cancer is preferably non-small cell lung cancer or small cell lung cancer, the myeloma is preferably multiple myeloma (MM), the autoimmune disease 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 Immune 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, Pulmonary Hemorrhage-Nephritic Syndrome, Graves' Disease, Guillain-Barré Syndrome (GBS), Hashimoto's Disease, Hidradenitis Suppurativa, Kawasaki Disease, Onychomycosis globulin nephropathy, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP), interstitial cystitis, lupus, lupus nephritis, membranous nephropathy, mixed connective tissue disease, morphea, Multiple sclerosis (MS), myasthenia gravis, narcolepsy, neuromyotonia, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, Scleroderma, xerophthalmia, Sjogren's syndrome, stiff man syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia and Wegener's granulomatosis, preferably lupus erythematosus Or systemic lupus erythematosus, the pemphigus is preferably pemphigus vulgaris, the liver cancer is preferably hepatocellular carcinoma, and 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.