WO2021121276A1

WO2021121276A1 - Fused tetracyclic derivative, preparation method therefor, and medical use thereof

Info

Publication number: WO2021121276A1
Application number: PCT/CN2020/136846
Authority: WO
Inventors: 李心; 董平; 付纪强; 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: 2019-12-17
Filing date: 2020-12-16
Publication date: 2021-06-24
Also published as: TW202128707A

Abstract

Disclosed are a fused tetracyclic derivative as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and the use thereof as an AKT1/2/3 (AKT pan) inhibitor and in the preparation of drugs for treating and/or preventing tumors.

Description

Condensed tetracyclic derivatives, preparation method thereof and application in medicine

Technical field

The present disclosure belongs to the field of medicine, and relates to a fused tetracyclic derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as AKT1/ The use of 2/3 (AKT pan) inhibitors and the use in the preparation of drugs for the treatment and prevention of tumors.

Background technique

Protein kinase B (PKB, also known as AKT) is at the center of PI3K/AKT/mTOR signal transduction in cells, and its function plays an important role in cell growth, survival, differentiation and metabolism. The PI3K signaling pathway participates in and regulates the expression of multiple oncogenes and anti-oncogenes. The excessive activation of the PI3K/AKT signaling pathway has been confirmed to be related to the occurrence of a variety of cancers.

In cells, AKT can be activated by a series of signals, including growth factors. When the receptor tyrosine kinase (receptor tyrosine kinase) on the cell membrane is activated by growth factors, it will activate downstream PI3K to phosphorylate phosphatidylinositol-4,5-biphosphate (phosphatidylinositol-4,5-biphosphate, PIP2) to form phosphatidylinositol-3,4,5-triphosphate (PIP3). Finally, phosphatidylinositol-dependent kinase 1 (PDK1) and AKT are recruited to the cell membrane, and then AKT is activated by PDK1. The mutation of PI3K and the deletion and mutation of the homologous Phosphatase and tensin homolog (PTEN) will continue to activate the AKT protein, so that the pathway is continuously activated. The role of AKT in cells is mainly to promote cell proliferation, cause cells to transform from benign to malignant, and promote cell movement and invasion, thereby causing tumor cell metastasis and dissemination. Moreover, the highly active phosphorylated AKT can also inhibit cell apoptosis, and participate in the mechanism of chemotherapy resistance, which affects the effect of clinical treatment. In clinical statistics, tumors with high activity of AKT account for 40% or more of different tumors.

There are three subtypes of AKT enzymes (AKT1, AKT2 and AKT3), and various studies have shown that they each have different functions in the body. The signal pathway activated by AKT1 mainly regulates cell proliferation and survival, while AKT2 is involved in cell invasion and migration, as well as the insulin-regulated blood glucose metabolism pathway. Although AKT3 gene knockout mice only show functions related to embryonic brain development, clinical studies have found that the expression of AKT3 is significantly increased in breast cancer and other tumors. In addition, preclinical in vitro studies have shown that breast cancer cells will develop drug resistance in the treatment of long-term AKT1/2 selective inhibitor MK2206, and the expression of AKT3 is significantly increased in the drug-resistant cells.

Inhibitors for AKT targets have been studied clinically for many years. The selective inhibitors of AKT1/2, MK2206 (Merck) and BAY1125976 (Bayer), have not been successful clinically due to curative effects and toxicity. However, in recent years, AKT1/2/3 (AKT pan) inhibitors AZD5363 (AZ) and GDC0068 (Roche) have achieved breakthrough results in phase 2 clinical trials. The combination of them and other anticancer drugs can treat triple-negative breast cancer and ER+ breast cancer. And the treatment of prostate cancer has produced obvious effects. At present, the two AKT1/2/3 (AKT pan) inhibitors AZD5363 and GDC0068 have successfully advanced to the phase 3 clinical phase.

Global cancer statistics in 2018 show that there are 18 million new cancer cases and 9.6 million cancer deaths worldwide, and the annual cancer incidence rate is on the rise. Among them, the top three cancers are lung cancer (11.6%), female breast cancer (11.6%), and prostate cancer (7.1%). In China, due to the huge population base in China, the number of female breast cancer incidence and death cases accounted for 11.2% and 9.2% of the global incidence and death respectively, ranking among the top in the world. Prostate cancer is a high-incidence cancer in the United States. It is estimated that there will be 11 million prostate cancer patients worldwide in 2022, of which about 3 million (28%) in the United States.

Patent applications for AKT inhibitors that have been published include WO2006/071819, US8377937, WO2008/075109, US2010120801 and WO2009006040.

Summary of the invention

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

among them:

Y is N atom or CR ² ;

Q is a CH or N atom; the condition is that when Y is CR ² , Q is a N atom;

Z is O atom or NR ³ ;

G ¹ and G ^{2 are the} same or different, and are each independently selected from CR ⁴ or N atoms;

R ⁰ is -C(O)CHR ⁵ R ⁶ or -C(O)NHCHR ⁵ R ⁶ ;

R ^{1 is} selected from hydrogen atom, halogen, alkyl and haloalkyl;

R ^{2 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR ⁷ R ⁸ , nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from amino, -NR ⁷ R ⁸ , halogen, alkoxy, haloalkyl, cyano, nitro, hydroxy, Substituted by one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{3 is} 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;

R ^{4 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;

R ^{5 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From -NR ⁹ R ¹⁰ , oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituted by one or more substituents in the aryl group and heteroaryl group;

R ^{6 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;

R ⁷ and R ^{8 are the} same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁹ and R ^{10 are the} same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally substituted by one or more selected from cycloalkyl, heterocyclyl, aryl and heteroaryl Substitution;

n is 0, 1, 2, 3, or 4.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{6 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino , Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents; R ⁹ and R ^{10 are the} same or different, and are each independently selected from hydrogen, halogen, alkyl, Alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is a N atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The conformer, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ¹ is a N atom; G ² is CR ⁴ ; R ^{4 is} as defined in the general formula (I).

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

among them:

Z, Y, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIaa) or general formula (IIbb) or its tautomer, meso form, and racemate , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

Z, Y, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (I).

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

among them:

R ⁰ is -C(O)CHR ⁵ R ⁶ ; preferably

Z, R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁹ and n are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIIaa) or general formula (IIIbb) or its tautomer, meso form, and racemate , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

Z, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV) or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R ⁰ is -C(O)NHCHR ⁵ R ⁶ ;

Z, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer R ² is -NR ⁷ R ⁸ ; R ⁷ and R ^{8 are the} same or different, and each independently is a hydrogen atom or an alkyl group; preferably, R ⁷ and R 8 are the same or different. R ^{8 is the} same or different and is each independently a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an O atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is -C(O)CHR ⁵ R ⁶ or -C(O)NHCHR ⁵ R ⁶ ; preferably

R ⁵ is an alkyl group, wherein the alkyl group is optionally substituted by one or more substituents ^{selected from hydroxyl group and -NR 9} R ¹⁰ ^{; R 9} and R ^{10 are the} same or different, and each independently is a hydrogen atom Or alkyl; R ⁶ is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl and haloalkoxy Substituents are substituted.

In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (IIaa) or general formula (IIbb) or its tautomer, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁰ is -C (O) CHR ⁵ R ⁶ or -C( O) NHCHR ⁵ R ⁶ ; R ⁵ is an alkyl group, wherein the alkyl group is optionally substituted by one or more substituents ^{selected from hydroxyl and -NR 9} R ¹⁰ ^{; R 9} and R ^{10 are the} same or different , Each independently selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl Substituted; R ⁶ is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally selected from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy Replaced.

R ⁵ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by one or more substituents selected from hydroxyl and -NR ⁹ R ¹⁰ ^{; R 9} and R ^{10 are the} same or Different, each independently selected from hydrogen atom, C _1-6 alkyl group and 3 to 6 membered cycloalkyl group, wherein said C _1-6 alkyl group is optionally selected from 3 to 6 membered cycloalkyl group, 3 to 6 membered cycloalkyl group, and 3 to 6 membered cycloalkyl group. A 6-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group are substituted by one or more substituents; R ⁶ is a 6 to 10-membered aryl group or a 5- to 10-membered heteroaryl group, wherein The 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 One or more substituents in the halogenated alkoxy group are substituted.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (III), general formula (IIIaa) or general formula (IIIbb) or its tautomer, meso, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁵ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is any Optionally substituted by -NR ⁹ R ¹⁰ ; R ⁹ and R ^{10 are the} same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group and a 3 to 6-membered cycloalkyl group, wherein the C _1-6 alkane The group is optionally substituted by one or more substituents selected from 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group; R ⁶ is 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein The 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 One or more substituents in the halogenated alkoxy group are substituted.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by a hydroxy group; R ⁶ is 6 to 10 members Aryl or 5 to 10 membered heteroaryl, wherein the 6 to 10 membered aryl or 5 to 10 membered heteroaryl is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 haloalkyl and C _1-6 haloalkoxy are substituted by one or more substituents.

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

among them:

R ¹ , R ⁴ , R ⁶ , R ⁹ and n are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (Vaa) or general formula (Vbb) or its tautomer, meso, racemate , Enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:

among them:

R ¹ , R ⁴ , R ⁶ , R ⁹ and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (III), general formula (IIIaa) or general formula (IIIbb) or its tautomer, meso, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹ is a hydrogen atom; R ⁴ is a hydrogen atom; R ⁰ is -C(O)NHCHR ⁵ R ⁶ ; R ⁵ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally ^{substituted by -NR 9} R ¹⁰ ; R ⁹ and R ^{10 are the} same or different, and are each independently selected from hydrogen atoms , C _1-6 alkyl and 3 to 6 membered cycloalkyl, wherein the C _1-6 alkyl is optionally selected from one or more of 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group R ⁶ is a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group, wherein the 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group is optionally selected from halogen, C _{One or more substituents of 1-6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; n is 0.

In some embodiments of the present disclosure, the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer R ¹ is a hydrogen atom; R ⁴ is a hydrogen atom; R ² is -NR ⁷ R ⁸ ; R ⁷ and R ^{8 are the} same or different, and are each independently A hydrogen atom or a C _1-6 alkyl group; R ⁰ is -C(O)NHCHR ⁵ R ⁶ ; R ⁵ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by a hydroxy group; R ⁶ is a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group, wherein the 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group is optionally selected from halogen, C _1-6 alkyl, C _{One or more substituents of 1-6} alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; n is 0.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (V), general formula (Vaa) or general formula (Vbb) or its tautomer, meso, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹ is a hydrogen atom; R ⁴ is a hydrogen atom; R ⁶ is a 6 to 10-membered aryl group Or a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C One or more substituents in _1-6 haloalkyl and C _1-6 ^{haloalkoxy; R 9 is} selected from hydrogen atom, C _1-6 alkyl and 3 to 6-membered cycloalkyl, wherein said The C _1-6 alkyl group is optionally substituted with one or more substituents selected from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups; n is zero.

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

Another aspect of the present disclosure relates to the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,

among them:

R ^w is an amino protecting group, preferably (trimethylsilyl)ethoxymethyl;

Y is N atom or CR ² ;

Q is a CH or N atom; the condition is that when Y is CR ² , Q is a N atom;

Z is O atom or NR ³ ;

G ¹ and G ^{2 are the} same or different and are each independently selected from CR ⁴ or N atom;

R ⁰ is -C(O)CHR ⁵ R ⁶ or -C(O)NHCHR ⁵ R ⁶ ;

R ^{1 is} selected from hydrogen atom, halogen, alkyl and haloalkyl;

R ^{5 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From -NR ⁹ R ¹⁰ , -OR ¹¹ , oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, One or more substituents in heterocyclic group, aryl group and heteroaryl group;

R ^{6 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;

R ⁹ and R ^{10 are the} same or different, and are each independently selected from a hydrogen atom, R ^m , halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from one of cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;

R ^{11 is} selected from hydrogen atom, R ⁿ , alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^m is an amino protecting group; preferably, R ^m is tert-butoxycarbonyl;

R ⁿ is a hydroxy protecting group; preferably, R ⁿ is a tert-butyldimethylsilyl group;

n is 0, 1, 2, 3, or 4.

In some embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ^{5 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino , Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl are each independently optionally selected from -NR ⁹ R ¹⁰ , oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, Substituted by one or more substituents among nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{6 is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents in;

R ⁹ and R ^{10 are the} same or different, and are each independently selected from a hydrogen atom, R ^m , halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^m is an amino protecting group, preferably, R ^m is a tert-butoxycarbonyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

Z, Y, R ⁰ , R ¹ , R ⁴ , R ^w and n are as defined in the general formula (IA).

In some embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIaaA) or general formula (IIbbA) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

In some embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

R ⁰ is -C(O)CHR ⁵ R ⁶ ; preferably

Z, R ¹ , R ⁴ , R ⁵ , R ⁶ , R ^w , R ^m , R ⁹ and n are as defined in the general formula (IA).

In some embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IVA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

among them:

R ⁰ is -C(O)NHCHR ⁵ R ⁶ ;

Z, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^w and n are as defined in the general formula (IA).

In some embodiments of the present disclosure, the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

R ^m is an amino protecting group, preferably tert-butoxycarbonyl;

R ¹ , R ⁴ , R ⁶ , R ⁹ , R ^w and n are as defined in the general formula (IA).

The compounds of the typical general formula (IA) of the present disclosure include, but are not limited to:

Wherein Boc is tert-butoxycarbonyl; SEM is (trimethylsilyl)ethoxymethyl; TBS is tert-butyldimethylsilyl.

Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IA) removes the amino protecting group to obtain the compound of general formula (I),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

G ¹ , G ² , Q, Z, Y, R ⁰ , R ¹ and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the general formula (IIA) removes the amino protecting group to obtain the compound of the general formula (II),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

Z, Y, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (II).

Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (IIaa) and general formula (IIbb) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (II) undergoes chiral resolution to obtain compounds of general formula (IIaa) and general formula (IIbb),

among them:

Z, Y, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the general formula (IIIA) is removed from the amino protecting group to obtain the compound of the general formula (III),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

Z, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (III).

Another aspect of the present disclosure relates to a preparation of compounds represented by general formula (IIIaa) and general formula (IIIbb) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (III) undergoes chiral resolution to obtain compounds of general formula (IIIaa) and general formula (IIIbb),

among them:

Z, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IVA) removes the amino protecting group to obtain the compound of general formula (IV),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

Z, R ⁰ , R ¹ , R ² , R ⁴ and n are as defined in the general formula (IV).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (VA) removes the amino protecting group to obtain the compound of general formula (V),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

R ^m is an amino protecting group; preferably tert-butoxycarbonyl;

R ¹ , R ⁴ , R ⁶ , R ⁹ and n are as defined in the general formula (V).

Another aspect of the present disclosure relates to a preparation of compounds represented by general formula (Vaa) and general formula (Vbb) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (V) undergoes chiral resolution to obtain compounds of general formula (Vaa) and general formula (Vbb),

among them:

R ¹ , R ⁴ , R ⁶ , R ⁹ and n are as defined in the general formula (V).

Another aspect of the present disclosure relates to a pharmaceutical composition containing the compound represented by the general formula (I) of the present disclosure or its tautomers, mesosomes, racemates, and enantiomers. Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The use of the pharmaceutically acceptable salt or the pharmaceutical composition containing the same in the preparation of a medicine for inhibiting AKT1/2/3 (AKTpan).

The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its pharmaceutically acceptable salt or pharmaceutical composition containing it in the preparation of a medicament for the treatment and/or prevention of tumors.

The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The use of its pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicament for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from ovarian cancer, breast cancer, prostate cancer, glioma, Glioma, stomach cancer, fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma , Bone cancer, uterine cancer, endometrial cancer, head and neck cancer, multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, thyroid tumor, bladder cancer and gallbladder cancer .

The present disclosure also relates to a method for inhibiting AKT1/2/3 (AKT pan), which comprises administering to a desired patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer or meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

The present disclosure also relates to a method for the treatment and/or prevention of tumors, which comprises administering to a desired patient a therapeutically or preventively effective amount of a compound represented by the general formula (I) or its tautomer, mesosome, exo Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

The present disclosure also relates to a method for the treatment and/or prevention of cancer, which comprises administering to a desired patient a therapeutically or preventively effective amount of a compound represented by general formula (I) or its tautomer, mesosome, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, wherein the cancer is preferably selected from ovarian cancer, breast cancer, Prostate cancer, glioma, glioma, stomach cancer, fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin Cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumors, multiple myeloma, lymphoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, Thyroid tumors, bladder cancer and gallbladder cancer.

The present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.

The present disclosure also relates to a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as an AKT1/2/3 (AKTpan) inhibitor.

The present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a drug for treating tumors.

The tumor described in the present disclosure is selected from melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, nerves Blastoma, glioma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor , Bladder cancer and gallbladder cancer.

The present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a medicine for the treatment of cancer; wherein the cancer is preferably selected from ovarian cancer, breast cancer, prostate cancer, glioma, glioma, Gastric cancer, fallopian tube cancer, lung cancer, peritoneal cancer, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterus Cancer, endometrial cancer, head and neck tumors, multiple myeloma, lymphoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.

The active compound can be formulated into a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer in a single dose. The unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.

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 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active substance and excipients for mixing suitable for preparing aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

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

By adding water, dispersible powders and granules suitable for preparing water suspensions can provide active ingredients and dispersing agents, wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing agents, wetting agents and suspending agents may also be added with other excipients such as sweetening agents, flavoring agents and coloring agents. These compositions are preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection preparation can be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing agents, wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

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 that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc. In addition, the optimal treatment method, such as the treatment mode, the daily dosage of the compound (I), or the type of pharmaceutically acceptable salt, can be verified according to the traditional treatment plan. The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1-1000 mg.

The present disclosure provides a fused four-ring AKT1/2/3 (AKTpan) inhibitor with a novel structure, which has a good inhibitory effect on AKT1, AKT2 and AKT3 enzymes.

Term Description

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

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

When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will understand, when the parameters are not critical, the numbers are usually given for illustrative purposes only, rather than limitations.

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 containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups are more preferably alkyl groups containing 1 to 6 carbon atoms. 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-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. 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, and sec-butyl. Group, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from the group consisting of H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl group, alkoxy group , Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents.

The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 ), more preferably an alkylene group 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 -), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl One or more substituents in the group, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above. Preferred are alkenyl groups containing 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferred are alkenyl groups containing 2 to 6 carbon atoms. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, and halogenated alkoxy groups. One or more substituents in the group, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl .

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above. Preference is given to alkynyl groups containing 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and alkynyl groups containing 2 to 6 carbon atoms are more preferred. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, and a halogenated alkoxy group. One or more substituents in the group, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3, 4, 5). , 6, 7, 8, 9, 10, 11, and 12), more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed 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 5-membered and 6-membered/6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro ring, fused ring and bridged ring) fused on an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably indanyl, tetrahydronaphthyl.

Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, sulfur, S( O) or S(O) ₂ heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), of which 1 to 4 (for example, 1, 2, 3, and 4) are hetero Atom; more preferably contains 3 to 8 ring atoms (such as 3, 4, 5, 6, 7 and 8), of which 1-3 (such as 1, 2 and 3) are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contain 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen, sulfur, and S (O) or S(O) ₂ heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, or 6-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" 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. One or more rings may contain one or more Double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O) ₂ and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent 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 double ring, 6 yuan/3 yuan, 6 yuan/4 yuan, 6-membered/5-membered and 6-membered/6-membered fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms It is a heteroatom selected from nitrogen, oxygen, sulfur, S(O) or S(O) ₂ , and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent The rings linked together in the structure are heterocyclic groups, non-limiting examples of which include:

The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl. The aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :

Aryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is a heteroaryl ring, and non-limiting examples thereof include :

Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group.

The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the removal of one hydrogen atom from the parent ring atom, or two residues derived from the same ring atom or two different ring atoms of the parent The residues derived from the removal of two hydrogen atoms are "divalent cycloalkyl", "divalent heterocyclic group", "arylene", and "heteroarylene".

The term "amino protecting group" is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro. The amino protecting group is preferably (trimethylsilyl)ethoxymethyl (SEM) and tert-butoxycarbonyl (Boc).

The term "hydroxyl protecting group" is a suitable group for protecting a hydroxyl group known in the art, see the document "Protective Groups in Organic Synthesis", 5th edition, TW Greene & P. GMWuts for the hydroxyl protecting group. As an example, preferably, the hydroxy protecting group can be (C _1-10 alkyl or aryl) ₃ silyl group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl group (TBS), tert-butyldiphenylsilyl, etc.; can be C _1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 alkoxy Substituted C _1-6 alkyl or phenyl substituted C _1-6 alkyl, most preferably C _1-4 alkoxy substituted C _1-4 alkyl, for example: methyl, tert-butyl, allyl , Benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C _1-10 alkyl or aryl) acyl, such as formyl , Acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C _1-6 alkyl or C _6-10 aryl)sulfonyl; can also be (C _1-6 alkoxy or C _{6 -10} aryloxy) carbonyl.

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

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

The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above.

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

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

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

The term "hydroxy" refers to the -OH group.

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

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

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to "=O".

The term "carbonyl" refers to C=O.

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

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

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to replacing hydrogen with "deuterium" or "tritium", or replacing ^{fluorine with 18} F-fluorine label ( ¹⁸ F isotope), or enriching ^{with 11} C-, ¹³ C- or ^{14 C-} Compounds in which carbon atoms ( ¹¹ C-, ¹³ C- or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C- or ¹⁴ C- isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.

Those skilled in the art can synthesize the compound of formula (I) in the deuterated form with reference to relevant literature. When preparing the deuterated form of the compound of formula (I), commercially available deuterated starting materials can be used, or conventional techniques can be used to synthesize with deuterated reagents. The deuterated reagents include but are not limited to deuterated borane and tri-deuterated boron. Alkyl tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.

"Optional" or "optionally" means that the event or environment described later can but need not occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiological/pharmaceutically acceptable Carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity.

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.

The term "pharmaceutically acceptable" as used herein refers to these compounds, materials, compositions and/or dosage forms, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or Other problems or complications have a reasonable benefit/risk ratio and are effective for the intended use.

Synthetic method of the compound 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, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof The preparation method of medicinal salt includes the following steps:

The compound of general formula (IA) is subjected to acidic conditions, the amino protecting group is removed to obtain the compound of general formula (I),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

Option II

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

Under acidic conditions, the compound of general formula (IIA) removes the amino protecting group to obtain the compound of general formula (II);

The compound of general formula (II) undergoes chiral resolution to obtain compounds of general formula (IIaa) and general formula (IIbb);

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

Z, Y, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (II).

third solution

The compound represented by the general formula (IIIaa) or the general formula (IIIbb) of the present disclosure or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or The preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:

The compound of general formula (IIIA) is subjected to acidic conditions, the amino protecting group is removed to obtain the compound of general formula (III);

The compound of general formula (III) undergoes chiral resolution to obtain compounds of general formula (IIIaa) and general formula (IIIbb);

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

Z, R ⁰ , R ¹ , R ⁴ and n are as defined in the general formula (III).

Option Four

The compound represented by the general formula (IV) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The preparation method of medicinal salt includes the following steps:

The compound of general formula (IVA) is removed under acidic conditions to obtain the compound of general formula (IV),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

Option Five

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

The compound of general formula (VA) is subjected to acidic conditions, the amino protecting group is removed to obtain the compound of general formula (V),

among them:

R ^w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl;

R ^m is an amino protecting group; preferably tert-butoxycarbonyl;

R ¹ , R ⁴ , R ⁶ , R ⁹ and n are as defined in the general formula (V).

The reagents that provide acidic conditions in the above synthesis scheme include but are not limited to 1,4-dioxane solution of trifluoroacetic acid, hydrochloric acid, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid , P-toluenesulfonic acid, Me ₃ SiCl and TMSOTf; preferably trifluoroacetic acid.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide and mixtures thereof.

Detailed ways

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

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} The NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), water ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis and determination use Agilent 1260 DAD high performance liquid chromatograph.

The HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

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 thin layer chromatography separation and purification product 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 value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by 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 Chemicals and other companies.

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

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

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

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

The microwave reaction uses the CEM Discover-S 908860 microwave reactor.

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

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethyl can also be added Basic or acidic reagents such as amine and acetic acid are used for adjustment.

Wherein Boc is tert-butoxycarbonyl; SEM is (trimethylsilyl)ethoxymethyl.

Example 1

(S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-((R)-7a,8,10,11-tetrahydro-4H-6-oxa-1, 3,4,9,11a-Pentazadibenzo[cd,f]azulene-9(7H)-yl)propan-1-one 1-P1

(S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-((S)-7a,8,10,11-tetrahydro-4H-6-oxa-1, 3,4,9,11a-Pentazadibenzo[cd,f]azulene-9(7H)-yl)propan-1-one 1-P2

first step

5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 1b

5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine 1a (4.00g, 17.21mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) dissolved in N,N'-dimethylformamide (15mL). The temperature was lowered to 0°C, sodium hydride (1.03 g, 25.75 mmol) was added, and the reaction was stirred for 10 minutes. Add 2-(trimethylsilyl)ethoxymethyl chloride (4.30 g, 25.79 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), and stir at room temperature for 14 hours. Under ice-water bath, add saturated ammonium chloride solution, extract with ethyl acetate, dry the organic phase and concentrate. The residue was purified by column chromatography with eluent system C to obtain the title compound 1b (6.18 g), yield: 99%.

MS m/z (ESI): 363.8 [M+1] ⁺ .

Second step

5-bromo 4-[1-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperazinyl)-4-yl]-7-((2-(trimethylsilyl)ethoxy)methyl Base)-7H-pyrrolo[2,3-d]pyrimidine 1d

Mix compound 1b (2.00g, 5.51mmol) and 1-tert-butoxycarbonyl-3-hydroxymethylpiperazine 1c (1.19g, 5.50mmol, Shanghai Beat Pharmaceutical Technology Co., Ltd.), add N,N-dimethyl Methyl formamide (10mL) and diisopropylethylamine (2.88g, 16.48mmol)), the temperature was raised to 100°C and reacted for 17 hours. The reaction solution was cooled, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain the title compound 1d (2.17 g), yield: 72%.

MS m/z (ESI): 543.9 [M+1] ⁺ .

third step

4-((2-(Trimethylsilyl)ethoxy)methyl)-7a,8,10,11-tetrahydro-4H-6-oxa-1,3,4,9,11a-penta Azodibenzo[cd,f]]azulene-9(7H)-carboxylic acid tert-butyl ester 1e

Combine compound 1d (2.17g, 4.00mmol) with cesium carbonate (2.60g, 7.98mmol), cuprous iodide (76mg, 0.40mmol), 8-hydroxyquinoline (116mg, 0.80mmol, Shanghai Better Pharmaceutical Co., Ltd.) Mix and add toluene (30 mL). In an argon atmosphere, the temperature was raised to 120°C and reacted for 24 hours. After cooling, it was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system C to obtain the title compound 1e (537 mg), yield: 29%.

MS m/z (ESI): 462.2 [M+1] ⁺ .

the fourth step

4-((2-(Trimethylsilyl)ethoxy)methyl)-7,7a,8,9,10,11-hexahydro-4H-6-oxa-1,3,4,9 ,11a-Pentazadibenzo[cd,f]]azulene 1f

Compound 1e (537 mg, 1.16 mmol) was dissolved in ultra-dry dichloromethane (10 mL), zinc bromide (1.83 g, 8.13 mmol) was added, and the reaction was carried out at room temperature for 17 hours. Under an ice-water bath, add 20 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (50 mL×5), and concentrate the organic phase under reduced pressure to obtain the title compound 1f (420 mg). The product was directly used in the next reaction without purification.

MS m/z (ESI): 362.1 [M+1] ⁺ .

the fifth step

((2S)-(2-(4-chlorophenyl)-3-oxo-3-(4-((2-(trimethylsilyl)ethoxy)methyl)-(7a,8, 10,11-tetrahydro-4H-6-oxa-1,3,4,9,11a-pentaazadibenzo[cd,f]azulene-9(7H)-yl)propyl) (isopropyl Yl) tert-butyl carbamate 1h

Compound 1f (390mg, 1.08mmol) was dissolved in N,N'-dimethylformamide (10mL), and (2S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-(4 -Chlorophenyl) propionic acid 1g (368mg, 1.0766mmol, synthesized according to the method disclosed in Org. Process Res. Dev. 2014, 18, 12, 1652-1666), 2-(7-azobenzotriazole) -Tetramethylurea hexafluorophosphate (410mg, 1.0783mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), diisopropylethylamine (697mg, 5.39mmol), react at room temperature for 20 hours. Add ethyl acetate to dilute and wash with saturated sodium bicarbonate solution. The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 1h (498 mg), yield: 67%.

MS m/z (ESI): 685.2 [M+1] ⁺ .

Sixth step

Compound 1h (80mg, 0.12mmol) was dissolved in trifluoroacetic acid (2mL) and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with tetrahydrofuran (2ml), saturated potassium carbonate solution (2ml) was added, and stirred at room temperature for 5 hours. Extract with dichloromethane (20mL×5), dry the organic phase and concentrate under reduced pressure. The residue is purified by preparative liquid chromatography (Instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase : A-water (10 mM ammonium bicarbonate), B-acetonitrile; flow rate: 30 mL/min column temperature: room temperature) to obtain title compounds 1-P1 (11 mg) and 1-P2 (12 mg), total yield: 35%.

Single configuration compound (shorter retention time)

MS m/z (ESI): 454.9 [M+1] ⁺ .

HPLC analysis: retention time 12.3 minutes, purity: 99.9% (column: X-Bridge, Prep30*150mm; 5um; mobile phase: A-water (10mM ammonium bicarbonate), B-acetonitrile; gradient ratio: A 20% -45%).

¹ H NMR (400MHz, CD ₃ OD) δ8.02-8.22 (m, 1H), 7.17-7.48 (m, 4H), 6.47-6.75 (m, 1H), 4.58-4.72 (m, 1H), 3.94 4.36(m,4H),3.57-3.84(m,1H),3.32-3.52(m,1H),3.02-3.28(m,3H),2.80-2.92(m,1H),2.82-3.02(m,2H) ), 2.55-2.80 (m, 1H), 1.03-1.14 (m, 6H).

Single configuration compound (longer retention time)

MS m/z (ESI): 455.0 [M+1] ⁺ .

HPLC analysis: retention time 13.9 minutes, purity: 96.2% (column: X-Bridge, Prep30*150mm; 5um; mobile phase: A-water (10mM ammonium bicarbonate), B-acetonitrile; gradient ratio: A 20% -45%).

¹ H NMR (400MHz, CD ₃ OD) δ 8.09-8.20 (m, 1H), 7.23-7.48 (m, 4H), 6.56-6.66 (m, 1H), 4.53-4.68 (m, 1H), 4.07- 4.43(m,3H),3.85-4.07(m,2H),3.37-3.60(m,2H),3.22-3.29(m,1H),3.05-3.19(m,1H),2.82-3.02(m,2H) ), 2.70-2.82 (m, 1H), 1.03-1.12 (m, 6H).

Example 2P

(S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-((S)-4a,5,7,8-tetrahydro-1H-3-oxa-1, 6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propan-1-one 2P

first step

(S)-4-(5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Tert-Butyl 3-(hydroxymethyl)piperazinyl-1-carboxylate 2b

Mix compound 1b (40.00g, 110.28mmol) and (S)-1-tert-butoxycarbonyl-3-hydroxymethylpiperazine 2a (25.00g, 115.59mmol, Nanjing Yaoshi Technology Co., Ltd.), add N, N '-Dimethylformamide (100mL), diisopropylethylamine (42.10g, 325.74mmol), heated to 120°C and reacted for 17 hours. After cooling, the reaction solution was concentrated and purified by column chromatography with eluent system C to obtain the title compound 2b (40.00 g), yield: 67%.

MS m/z (ESI): 543.9 [M+1] ⁺ .

Second step

(S)-1-((2-(Trimethylsilyl)ethoxy)methyl)-4a,5,7,8-tetrahydro-1H-3-oxa-1,6,8a,9 ,11-Pentazadibenzo[cd,f]azulene-6(4H)-carboxylic acid tert-butyl ester 2c

Combine compound 2b (30.33g, 55.90mmol) with cesium carbonate (36.43g, 111.81mmol), cuprous iodide (3.19g, 16.77mmol), 8-hydroxyquinoline (2.43g, 16.77mmol), Shanghai Better Pharmaceutical Co., Ltd. Company) mixed, added toluene (110mL), heated to 120°C under the protection of argon, and reacted overnight. After cooling, it was filtered using Celite. After the filtrate was concentrated, it was purified by column chromatography with eluent system C to obtain the title compound 2c (10.28 g), yield: 40%.

MS m/z (ESI): 462.2 [M+1] ⁺ .

third step

(S)-1-((2-(Trimethylsilyl)ethoxy)methyl)-4,4a,5,6,7,8-hexahydro-1H-3-oxa-1,6 ,8a,9,11-Pentazadibenzo[cd,f]]azulene 2d

Compound 2c (10.28 g, 22.30 mmol) was dissolved in ultra-dry dichloromethane (200 mL), zinc bromide (25.36 g, 112.61 mmol) was added, and the reaction was carried out at room temperature for 17 hours. Under ice water bath, add saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (200 mL×5), and the organic phase was concentrated and purified by column chromatography with eluent system A to obtain the title compound 2d (7.56 g), yield: 94%.

MS m/z (ESI): 362.1 [M+1] ⁺ .

the fourth step

((S)-2-(4-chlorophenyl)-3-oxo-3-((S)-1-((2-(trimethylsilyl)ethoxy)methyl)-4a, 5,7,8-Tetrahydrotert-butyl-1H-3-oxa-1,6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propane Yl) (isopropyl) tert-butyl carbamate 2e

Compound 2d (4.38g, 12.14mmol) was dissolved in N,N'-dimethylformamide (50mL), and (2S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-( 4-chlorophenyl) propionic acid 1g (3.90g, 11.41mmol, synthesized according to the method disclosed in Org.Process Res.Dev.2014,18,12,1652-1666), 2-(7-azobenzotriazide Azole)-tetramethylurea hexafluorophosphate (5.55g, 17.07mmol), diisopropylethylamine (4.41g, 34.18mmol), react at room temperature for 20 hours. Add ethyl acetate to dilute and wash with saturated sodium bicarbonate solution. The organic phase was dried and concentrated under reduced pressure, and purified by column chromatography with eluent system C to obtain the title compound 2e (5.50 g), yield: 70%.

MS m/z (ESI): 685.2 [M+1] ⁺ .

the fifth step

Compound 2e (5.50 g, 8.02 mmol) was dissolved in trifluoroacetic acid (50 mL) and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Dilute with methanol (50 ml), add saturated potassium carbonate solution (50 mL), and stir at room temperature for 5 hours. Extract with dichloromethane (100mL×5), dry the organic phase and concentrate under reduced pressure. The residue is purified by liquid preparation (Instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase: A -Water (13mM trifluoroacetic acid) B-acetonitrile flow rate: 30mL/min column temperature: room temperature), sodium bicarbonate neutralized, extracted with dichloromethane, dried and concentrated to obtain the title compound 2P (2.50g), total yield : 68%.

MS m/z (ESI): 454.9 [M+1] ⁺ .

Example 3-P1, 3-P2

(S)-2-(4-chlorophenyl)-3-(cyclopropylamino)-1-((S)-4a,5,7,8-tetrahydro-1H-3-oxa-1, 6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propan-1-one 3-P1

(R)-2-(4-chlorophenyl)-3-(cyclopropylamino)-1-((S)-4a,5,7,8-tetrahydro-1H-3-oxa-1, 6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propan-1-one 3-P2

first step

3-((tert-Butoxycarbonyl)(cyclopropyl)amino)-2-(4-chlorophenyl) ethyl propionate 3b

To ethyl 2-(4-chlorophenyl)acrylate 3a (1.00g, 4.74mmol, synthesized according to the method disclosed in Org. Lett. 2017, 19, 19, 5216-5219) was added cyclopropylamine (1.35g, 23.64mmol) and stirred at 30°C overnight. After concentration, it was dissolved in dichloromethane (15 mL), triethylamine (2.39 g, 23.62 mmol) and di-tert-butyl dicarbonate (5.18 g, 23.73 mmol) were added under ice-water bath, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (100 mL), washed with sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 3b (1.15g), yield: 66%.

MS m/z (ESI): 268.1 [M-100+1] ⁺ .

Second step

3-((tert-Butoxycarbonyl)(cyclopropyl)amino)-2-(4-chlorophenyl)propionic acid 3c

Compound 3b (1.15 g, 3.12 mmol) was added with water (1.5 mL), methanol (6 mL), sodium hydroxide (625 mg, 15.62 mmol), and reacted at room temperature overnight. Under ice-water bath, 2N hydrochloric acid was adjusted to acidity, extracted with dichloromethane (50mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 3c (1.05g). The product was not further purified. , Directly used in the next reaction.

MS m/z(ESI): 338.0[M-1] ^- .

third step

(2-(4-chlorophenyl)-3-oxo-3-((S)-1-((2-(trimethylsilyl)ethoxy)methyl)-4a,5,7, 8-Tetrahydro-1H-3-oxa-1,6,8a,9,11-pentaazadibenzo[cd,f]azulene-6(4H)-yl)propyl)(cyclopropyl) Tert-butyl carbamate 3d

Compound 2d (191mg, 0.53mmol) was dissolved in N,N'-dimethylformamide (2mL), compound 3c (150mg, 0.44mmol), 2-(7-azobenzotriazole)- Tetramethylurea hexafluorophosphate (201mg, 0.53mmol) and diisopropylethylamine (285mg, 2.20mmol) were reacted at room temperature for 20 hours. Add ethyl acetate to dilute and wash with saturated sodium bicarbonate solution. The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 3d (193 mg), yield: 64%.

MS m/z (ESI): 683.2 [M+1] ⁺ .

the fourth step

Compound 3d (100 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (4 mL), and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Dilute with methanol (50 mL), add saturated potassium carbonate solution (50 mL), and stir at room temperature for 5 hours. Extract with dichloromethane (100mL×5), dry the organic phase and concentrate under reduced pressure. The residue is purified by preparative liquid chromatography (Instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase : A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; column temperature: room temperature) to obtain the title compound (10mg, 10mg), total yield: 24%.

Single configuration compound (shorter retention time)

MS m/z (ESI): 453.1 [M+1] ⁺ .

HPLC analysis: retention time 10.04 minutes, purity: 91% (column: X-Bridge, Prep 30*150mm; 5um; mobile phase: A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; Gradient ratio: B 16%-31%).

¹ H NMR (500MHz, CD ₃ OD) δ 8.27-8.30 (m, 1H), 7.27-7.49 (m, 4H), 6.76-6.80 (m, 1H), 4.41-4.96 (m, 4H), 4.02- 4.25 (m, 2H), 3.46-3.90 (m, 4H), 2.76-2.84 (m, 2H), 1.25-1.41 (m, 1H), 0.86-0.96 (m, 4H).

Single configuration compound (longer retention time)

MS m/z (ESI): 453.1 [M+1] ⁺ .

HPLC analysis: retention time 11.49 minutes, purity: 95% (column: X-Bridge, Prep 30*150mm; 5um; A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min, gradient ratio : B 16%-31%).

¹ H NMR (500MHz, CD ₃ OD) δ8.31-8.34 (m, 1H), 7.33-7.52 (m, 4H), 6.83-6.85 (m, 1H), 4.38-4.66 (m, 4H), 3.93 4.27(m,3H),3.59-4.85(m,2H),3.35-3.39(m,1H),3.11-3.25(m,1H),2.79-2.84(m,1H),1.30-1.36(m,1H) ), 0.89-0.98 (m, 4H).

Example 4-P1, 4-P2

(S)-2-(4-chlorophenyl)-3-((cyclopropylmethyl)amino)-1-((S)-4a,5,7,8-tetrahydro-1H-3-oxy Hetero-1,6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propan-1-one 4-P1

(R)-2-(4-chlorophenyl)-3-((cyclopropylmethyl)amino)-1-((S)-4a,5,7,8-tetrahydro-1H-3-oxy Hetero-1,6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propan-1-one 4-P2

first step

3-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)-2-(4-chlorophenyl) ethyl propionate 4a

To ethyl 2-(4-chlorophenyl)acrylate 3a (1.07g, 5.08mmol, synthesized according to the method disclosed in Org. Lett. 2017, 19, 19, 5216-5219) was added cyclopropylmethylamine (1.80g , 25.31mmol), stirred at 30°C overnight. After concentration, it was dissolved in dichloromethane (15 mL), triethylamine (2.56 g, 25.30 mmol) and di-tert-butyl dicarbonate (5.54 g, 25.38 mmol) were added under ice-water bath, and reacted at room temperature overnight. Dilute with dichloromethane (100 mL), wash with sodium bicarbonate, dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue is purified by column chromatography with eluent system C to obtain the title compound 4a (1.56 g), yield: 80%.

MS m/z (ESI): 282.1 [M-100+1] ⁺ .

Second step

3-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propionic acid 4b

Compound 4a (1.56 g, 4.08 mmol) was added with water (2 mL), methanol (8 mL), sodium hydroxide (817 mg, 20.42 mmol), and reacted at room temperature overnight. Under ice water bath, 2N hydrochloric acid was adjusted to acidity, extracted with dichloromethane (50mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 4b (1.44g). The product was not further purified. , Directly used in the next reaction.

MS m/z (ESI): 376.0 [M+23] ⁺ .

third step

(2-(4-chlorophenyl)-3-oxo-3-((S)-1-((2-(trimethylsilyl)ethoxy)methyl)-4a,5,7, 8-Tetrahydrotert-butyl-1H-3-oxa-1,6,8a,9,11-pentaazadibenzo[cd,f]azulene-6(4H)-yl)propyl) (ring (Propylmethyl) tert-butyl carbamate 4c

Compound 2d (184mg, 0.51mmol) was dissolved in N,N'-dimethylformamide (2mL), and compound 4b (150mg, 0.42mmol), 2-(7-azobenzotriazole)- Tetramethylurea hexafluorophosphate (161 mg, 0.42 mmol) and diisopropylethylamine (274 mg, 2.12 mmol) were reacted at room temperature for 20 hours. Add ethyl acetate to dilute and wash with saturated sodium bicarbonate solution. The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 4c (189 mg), yield: 64%.

MS m/z (ESI): 697.2 [M+1] ⁺ .

the fourth step

Compound 4c (160 mg, 0.23 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (4 mL), and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with methanol (50 mL), saturated potassium carbonate solution (50 mL) was added, and stirred at room temperature for 5 hours. Extract with dichloromethane (100mL×5), dry the organic phase and concentrate under reduced pressure. The residue is purified by preparative liquid chromatography (Instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase : A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; column temperature: room temperature) to obtain the title compound (5mg, 5mg), total yield: 7%.

Single configuration compound (shorter retention time)

MS m/z (ESI): 467.1 [M+1] ⁺ .

HPLC analysis: retention time 13.27 minutes, purity: 91% (column: X-Bridge, Prep 30*150mm; 5um; mobile phase: A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; Gradient ratio: B 15%-30%).

¹ H NMR (500MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.41-7.49 (m, 2H), 7.24-7.32 (m, 2H), 6.80-6.84 (m, 1H), 4.56-4.70 ( m,2H),4.44-4.49(m,2H),4.24-4.28(m,1H),4.04-4.12(m,1H),3.62-3.72(m,2H),3.23-3.33(m,4H), 2.93-3.03 (m, 2H), 1.1-1.18 (m, 1H), 0.7-0.73 (m, 2H), 0.41-0.43 (m, 2H).

Single configuration compound (longer retention time)

MS m/z (ESI): 467.1 [M+1] ⁺ .

HPLC analysis: retention time 14.73 minutes, purity: 95% (column: X-Bridge, Prep 30*150mm; 5um; A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; gradient ratio : A 15%-30%).

¹ H NMR (500MHz, CD ₃ OD) δ8.36 (s, 1H), 7.41-7.52 (m, 3H), 7.24-7.32 (m, 1H), 6.84-6.87 (m, 1H), 4.39-4.68 ( m,4H),3.94-4.18(m,2H),3.61-3.74(m,2H),3.25-3.31(m,2H),2.92-3.04(m,2H),1.30-1.35(m,2H), 1.11-1.75 (m, 1H), 0.71-0.74 (m, 2H), 0.41-0.44 (m, 2H).

Example 5-P1 or 5-P2

(S)-3-amino-2-(4-chlorophenyl)-1-((S)-4a,5,7,8-tetrahydro-1H-3-oxa-1,6,8a,9 ,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propan-1-one 5-P1

or

(R)-3-amino-2-(4-chlorophenyl)-1-((S)-4a,5,7,8-tetrahydro-1H-3-oxa-1,6,8a,9 ,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propan-1-one 5-P2

first step

(R)-3-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)propionic acid 5-b1

or

(S)-3-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)propionic acid 5-b2

3-amino-2-(4-chlorophenyl)propionic acid 5a (1g, 5.01mmol, Amate Reagent Co., Ltd.) was dissolved in methanol (10mL) and water (5mL), and sodium bicarbonate (2.1g, 25.00mmol), add di-tert-butyl dicarbonate (1.2g, 5.50mmol), stir overnight at room temperature, quench by adding water, and adjust PH=3 with dilute hydrochloric acid. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture (1.20 g). Take part of the product (779mg) for chiral resolution (instrument model: Shimadzu LC-20AD column: CHIRALPAK AY-3 (AY30CD-TJ004), Prep 0.46cm ID×15cm L; 5ul; mobile phase: n-hexane/ethanol/ Acetic acid=90/10/0.1(V/V/V); flow rate: 1.0ml/min; column temperature: room temperature), to obtain title compound 5-b1 or 5-b2 (353mg) with shorter retention time (3.3 minutes) , The yield is 36%, and the title compound 5-b1 or 5-b2 (378 mg) with a longer retention time (4.6 minutes), the yield is 39%. Take the longer retention time product for the next reaction.

MS m/z(ESI): 298.1[M-1] ^- .

Second step

((S)-2-(4-chlorophenyl)-3-oxo-3-((S)-1-((2-(trimethylsilyl)ethoxy)methyl)-4a, 5,7,8-Tetrahydro-1H-3-oxa-1,6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propyl)amino Tert-Butyl formate 5-c1

or

((R)-2-(4-chlorophenyl)-3-oxo-3-((S)-1-((2-(trimethylsilyl)ethoxy)methyl)-4a, 5,7,8-Tetrahydro-1H-3-oxa-1,6,8a,9,11-Pentazadibenzo[cd,f]azulene-6(4H)-yl)propyl)amino Tert-Butyl formate 5-c2

Dissolve compound 2d (60mg, 0.17mmol) in N,N'-dimethylformamide (2mL), add compound 5-b1 or 5-b2 (50mg, 0.17mmol), 2-(7-azobenzene) Triazole)-tetramethylurea hexafluorophosphate (76mg, 0.20mmol), diisopropylethylamine (64mg, 0.50mmol), react at room temperature for 20 hours. Add ethyl acetate to dilute and wash with saturated sodium bicarbonate solution. The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 5-c1 or 5-c2 (107 mg), yield: 99%.

MS m/z (ESI): 643.1 [M+1] ⁺ .

third step

or

Compound 5-c1 or 5-c2 (50 mg, 0.077 mmol) was dissolved in trifluoroacetic acid (1 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with methanol (1 mL), saturated potassium carbonate solution (1 mL) was added, and the mixture was stirred at room temperature for 5 hours. After filtration, it was purified by preparative liquid chromatography (instrument model: Gilson 281 column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase: A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL /min; column temperature: room temperature) to obtain the title compound 5-P1 or 5-P2 (10 mg), yield: 31%.

MS m/z (ESI): 413.0 [M+1] ⁺ .

¹ H NMR(500MHz,CD ₃ OD)δ8.13(d,J=14.7Hz,1H), 7.47–7.36(m,2H), 7.35–7.21(m,2H), 6.61(d,J=10.9Hz) ,1H),4.67–4.53(m,1H),4.45–4.24(m,1H),4.13–3.85(m,4H),3.59–3.47(m,1H),3.41(t,J=12.4Hz,1H ), 3.22 (t, J = 10.9 Hz, 1H), 3.17–3.04 (m, 1H), 3.01–2.90 (m, 1H), 2.88–2.77 (m, 1H).

Example 6-P1 or 6-P2

(4aS,6R)-6-amino-N-((S)-1-(4-chlorophenyl)-3-hydroxypropyl)-4,4a,5,6,7,8-hexahydro-1H -3-oxa-1,8a, 9,11-tetraazadibenzo[cd,f]azulene-6-carboxamide 6-P1

or

(4aS,6S)-6-amino-N-((S)-1-(4-chlorophenyl)-3-hydroxypropyl)-4,4a,5,6,7,8-hexahydro-1H -3-oxa-1,8a,9,11-tetraazadibenzo[cd,f]azulene-6-carboxamide 6-P2

first step

(2S)-2-(Hydroxymethyl)piperidin-4-ol 6b

(S)-1-(tert-Butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid 6a (7.00g, 28.54mmol, Shanghai Beat Reagent Co., Ltd.) was dissolved in tetrahydrofuran (50mL) and added under ice water bath Borane in tetrahydrofuran solution (1M, 213.94 mL, Anaiji Chemical Technology (Shanghai) Co., Ltd.), react at room temperature for 2 days. It was quenched by adding methanol under ice-water bath, concentrated and purified by column chromatography with eluent system A to obtain the crude product (6.60 g). The product was directly used in the next step without further purification.

The 1,4-dioxane solution (4M, 49.98 mL) of hydrochloric acid was added to the above crude product, reacted at room temperature for 1 hour, and concentrated to obtain the title compound 6b (3.74 g). The product was directly used in the next step without further purification.

MS m/z (ESI): 132.1 [M+1] ⁺ .

Second step

(2S)-1-(5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2-(hydroxymethyl)piperidine-4-ol 6c

Compound 6b (3.74g, 28.51mmol) was mixed with compound 1b (11.37g, 31.34mmol), diisopropylethylamine (18.42g, 142.52mmol), sodium bicarbonate (4.79g, 57.01mmol), added N, N-Dimethylformamide (25mL) was heated to 120°C and reacted overnight. After cooling, it was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system C to obtain the title compound 6c (6.19 g) with a yield of 47%.

MS m/z (ESI): 456.9 [M+1] ⁺ .

third step

(4aS)-1-(((2-(Trimethylsilyl)ethoxy)methyl)-4,4a,5,6,7,8-hexahydro-1H-3-oxa-1, 8a,9,11-tetraazadibenzo[cd,f]azulene-6-ol 6d

Combine compound 6c (3.63g, 7.93mmol) with cesium carbonate (7.75g, 23.78mmol), cuprous iodide (453m, 2.38mmol), 8-hydroxyquinoline (345mg, 2.38mmol, Shanghai Better Pharmaceutical Co., Ltd.) After mixing, toluene (7 mL) was added, and the temperature was raised to 120° C. under a nitrogen atmosphere to react for 24 hours. After cooling, a pad of Celite was filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography with eluent system C to obtain the title compound 6d (1.67 g), yield: 56%.

MS m/z (ESI): 377.1 [M+1] ⁺ .

the fourth step

(S)-1-((2-(Trimethylsilyl)ethoxy)methyl)-4a,5,7,8-tetrahydro-1H-3-oxa-1,8a,9,11 -Tetraazadibenzo[cd,f]azulene-6(4H)-one 6e

Compound 6d (1.67g, 4.43mmol) was dissolved in dichloromethane (13mL), pyridine (7.14mL, 88.75mmol) was added, Dess-Martin oxidant (3.20g, 7.54mmol) was added under ice water bath, and the reaction was carried out at room temperature for 3 hour. Add ethyl acetate (100 mL) to dilute under ice-water bath, quench with saturated sodium thiosulfate solution, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is chromatographed with column chromatography as eluent System C was purified to obtain the title compound 6e (828mg), yield: 50%.

MS m/z (ESI): 375.0 [M+1] ⁺ .

the fifth step

(4aS,4'R)-1-(((2-(Trimethylsilyl)ethoxy)methyl)-1,4,4a,5,7,8-hexahydrospiro[3-oxa -1,8a,9,11-tetraazadibenzo[cd,f]azulene-6,4'-imidazolidine]-2',5'-dione 6-f1

(4aS,4'S)-1-(((2-(Trimethylsilyl)ethoxy)methyl)-1,4,4a,5,7,8-hexahydrospiro[3-oxa-1 ,8a,9,11-tetraazadibenzo[cd,f]azulene-6,4'-imidazolidine]-2',5'-dione 6-f2

Dissolve compound 6e (828mg, 2.21mmol) in ethanol (8mL) and water (8mL), add trimethylsilyl cyanide (0.83mL, 6.63mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), ammonium carbonate (1.06g) , 11.03mmol), react at 60°C overnight. After cooling, it was concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compounds 6-f1 and 6-f2. The compound with long retention time is 425mg, yield: 43%; the compound with short retention time is 379mg, yield: 39% (LC-MS analysis: Column: ACQUITY UPLC BEHC18 1.7um 2.1*50mm; mobile phase: A- Water (v/v 1‰ formic acid), B-acetonitrile (v/v 1‰ formic acid), gradient ratio: B 10%-95%, total time 3.5 minutes. The shorter retention time is 1.70 minutes, and the longer retention time Bit is 1.74 minutes).

MS m/z (ESI): 445.0 [M+1] ⁺ .

Sixth step

(S)-3-amino-3-(4-chlorophenyl)-1-propanol 6h

Dissolve (S)-3-amino-3-(4-chlorophenyl)propionic acid 6g (10g, 50.09mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) in tetrahydrofuran (100mL), add borane dropwise under ice water bath Tetrahydrofuran solution (175.32mL, 175.32mmol, 1M, Anaiji Chemical Technology (Shanghai) Co., Ltd.), react at room temperature overnight. Under ice-water bath, methanol was added for quenching, and after concentration, the residue was purified by column chromatography with eluent system A to obtain the title compound 6h (5g) with a yield of 54%.

MS m/z (ESI): 186.1 [M+1] ⁺ .

Seventh step

(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorophenyl)prop-1-amine 6i

Compound 6h (2.5g, 13.47mmol) was dissolved in dichloromethane (20mL), imidazole (1.82g, 26.67mmol) was added, and tert-butyldimethylchlorosilane (2.5g, 16.58mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), react overnight at room temperature. It was quenched by adding water, extracted with dichloromethane (50mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 6i (3.1g), the yield was 76%.

MS m/z (ESI): 300.1 [M+1] ⁺ .

Eighth step

(4aS,6R)-6-amino-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,4a,5,6,7,8-hexahydro-1H-3 -Oxa-1,8a,9,11-tetraazadibenzo[cd,f]azulene-6-carboxylic acid 6-j1

or

(4aS,6S)-6-amino-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,4a,5,6,7,8-hexahydro-1H-3 -Oxa-1,8a,9,11-tetraazadibenzo[cd,f]azulene-6-carboxylic acid 6-j2

The compound 6-f1 or 6-f2 (410 mg, 0.92 mmol) obtained in the fifth step with a retention time of 1.74 minutes (410 mg, 0.92 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.03 ml, 7.37 mmol) and 4-diethylamine were added. Methylaminopyridine (112 mg, 0.92 mmol) and di-tert-butyl dicarbonate (805 mg, 3.69 mmol) were reacted at room temperature overnight. After concentration, a crude yellow liquid (502 mg) was obtained, and the product was directly used in the next reaction without purification.

A water (2 mL) solution of potassium hydroxide (4.48 g, 9.98 mmol) was added to the above crude product, and the mixture was heated and stirred at 120° C. until the reaction of all the raw materials was complete. After cooling, add hydrochloric acid (6N) under an ice water bath to adjust the pH to 6-7. After concentration, add a mixed solvent (dichloromethane: methanol = 1:1) to dissolve, filter, and concentrate to obtain the title compound 6-j1 or 6-i2 (386mg), the product was directly used in the next reaction without purification.

MS m/z (ESI): 420.2 [M+1] ⁺ .

Step 9

(4aS,6R)-6-amino-N-(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorophenyl)propyl)-1-(( 2-(Trimethylsilyl)ethoxy)methyl)-4,4a,5,6,7,8-hexahydro-1H-3-oxa-1,8a,9,11-tetraazadi Benzo[cd,f]azulene-6-carboxamide 6-k1

or

(4aR,6R)-6-amino-N-(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorophenyl)propyl)-1-(( 2-(Trimethylsilyl)ethoxy)methyl)-4,4a,5,6,7,8-hexahydro-1H-3-oxa-1,8a,9,11-tetraazadi Benzo[cd,f]azulene-6-carboxamide 6-k2

Compound 6-j1 or 6-j2 (386mg, 0.92mmol) was dissolved in N,N-dimethylformamide (10mL), compound 6i (303mg, 1.01mmol), O-(7-azabenzotriazole) were added Azol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (419mg, 1.10mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), diisopropylethylamine ( 804mL, 4.60mmol), react at room temperature overnight. It was diluted with dichloromethane (100 mL), washed with saturated sodium chloride solution, dried and concentrated under reduced pressure to obtain the title compound 6-k1 or 6-k2 (645 mg), which was directly used in the next reaction without purification.

MS m/z (ESI): 701.3 [M+1] ⁺ .

Tenth step

(4aS,6R)-6-amino-N-((S)-1-(4-chlorophenyl)-3-hydroxypropyl)-4,4a,5,6,7,8-hexahydro-1H -3-oxa-1,8a,9,11-tetraazadibenzo[cd,f]azulene-6-carboxamide 6-P1

or

Compound 6-k1 or 6-k2 (645 mg, 0.92 mmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Dilute with methanol (3 mL), add saturated potassium carbonate (635 mg, 4.59 mmol) solution (2 mL), and stir at room temperature for 5 hours. After concentration, add dichloromethane and methanol to dissolve, filter and concentrate under reduced pressure. The residue is purified by preparative liquid chromatography (instrument model: Gilson 281 column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase: A -Water (v/v 1‰ trifluoroacetic acid), B-acetonitrile; flow rate: 30 mL/min; column temperature: room temperature) to obtain the title compound 6-P1 or 6-P2 (52 mg), yield: 12%.

MS m/z (ESI): 457.2 [M+1] ⁺ .

HPLC analysis: retention time 17.7 minutes, purity: 98.2% (column: X-Bridge, Prep30*150mm; 5um; mobile phase: A-water (v/v 1‰ trifluoroacetic acid), B-acetonitrile; gradient ratio : A 90%-72%).

¹ H NMR (500MHz, CD ₃ OD) 8.13 (s, 1H), δ 7.42–7.32 (m, 4H), 6.58 (s, 1H), 5.07 (t, J = 7.2Hz, 1H), 4.95–4.89 (m,1H), 4.27--4.20(m,2H), 4.08--4.02(m,1H), 3.65--3.54(m,2H), 3.35--3.28(m,1H), 2.23--2.18(m,1H) , 2.11 (d, J=13.7 Hz, 1H), 2.05-1.99 (m, 2H), 1.69 (t, J=13.0 Hz, 1H), 1.51 (td, J=13.3, 4.6 Hz, 1H).

Test case:

Biological evaluation

Test Example 1. Evaluation of AKT1/AKT2/AKT3 Enzymology Experiments by Compounds of the Present Disclosure

The following method was used to determine the inhibitory effect of the compounds of the present disclosure on AKT1/AKT2/AKT3 kinase activity in vitro.

experimental method

The enzymatic activities of AKT1 (Invitrogen, P2999), AKT2 (Invitrogen, PV3184) and AKT3 (Invitrogen, PV3185) were measured using the KinEASE-STK S3 kit (Cisbio, 62ST3PEC). First, use DMSO to dilute the compound to be tested in a 3-fold gradient starting from 500 μM, with a total of 11 concentration points. The 5× buffer in the kit was diluted to 1× buffer, and DTT (Sigma, 43816-10ML) and MgCl _{2 were added} to make the buffer contain 1 mM DTT and 5 mM MgCl ₂ . The compound was diluted 20 times with 1× buffer for use. Dilute AKT1/AKT2/AKT3 kinase with 1× buffer to obtain enzyme solution. Dilute ATP (Invitrogen, PV3227) and S3-biotin in the kit with 1× buffer to obtain a substrate ATP mixture solution for use. Add 2 μL of enzyme solution and 4 μL of compound solution to each well of a 384-well plate (Corning, 4513), incubate at room temperature for 30 minutes, then add 4 μL of ATP and S3-biotin mixture solution, and incubate at room temperature for 90 minutes. The conditions of the AKT1 enzyme reaction are: the final concentration of enzyme is 2nM, the final concentration of ATP is 10μM, and the final concentration of S3-biotin is 2μM. The conditions of the AKT2 enzyme reaction are: the final concentration of enzyme is 5nM, the final concentration of ATP is 10μM, and the final concentration of S3-biotin is 2μM. The conditions of the AKT3 enzyme reaction are: the final concentration of enzyme is 0.4 nM, the final concentration of ATP is 45 μM, and the final concentration of S3-biotin is 2 μM. Use the detection buffer in the kit to dilute S3-cryptate and Streptavidin-XL665 to prepare a detection solution. After incubation, add 10μL of detection solution to each well, the final concentration of S3-cryptate is 200 times diluted with the mother solution, and the final concentration of Streptavidin-XL665 is 125nM. Incubate at room temperature for 60 minutes, use the HTRF module of the multi-functional microplate detector (BMG Labtech, PHERAstar FS) to read the signal values of 337nm excitation, 650nm and 620nm emission, and multiply the reading ratio by 10000 to obtain the ratio. Use Graphpad Prism software according to The concentration and ratio of the compound were used to draw a dose-response curve, and the IC ₅₀ value of the compound's inhibitory activity was calculated.

Experimental result

The inhibitory activity of the compounds of the present disclosure on the AKT1/AKT2/AKT3 enzyme can be determined by the above test, and the measured IC ₅₀ value is shown in Table 1.

Table 1 Compound _IC50 value for the disclosure AKT1 / AKT2 / AKT3 inhibition of the IC.

Conclusion: The compound of the present disclosure has a good inhibitory effect on AKT1/AKT2/AKT3 enzymes.

Claims

A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salt:

among them:

Y is N atom or CR 2 ;

Q is a CH or N atom; the condition is that when Y is CR 2 , Q is a N atom;

Z is O atom or NR 3 ;

G 1 and G 2 are the same or different, and are each independently selected from CR 4 or N atoms;

R 0 is -C(O)CHR 5 R 6 or -C(O)NHCHR 5 R 6 ;

R 1 is selected from hydrogen atom, halogen, alkyl and haloalkyl;

R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR 7 R 8 , nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from amino, -NR 7 R 8 , halogen, alkoxy, haloalkyl, cyano, nitro, hydroxy, Substituted by one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 3 is 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;

R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;

R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From -NR 9 R 10 , oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituted by one or more substituents in the aryl group and heteroaryl group;

R 6 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;

R 7 and R 8 are the same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 9 and R 10 are the same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally substituted by one or more selected from cycloalkyl, heterocyclyl, aryl and heteroaryl Substitution;

n is 0, 1, 2, 3, or 4.
The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein Q is a N atom.
The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, G 1 is a N atom; G 2 is CR 4 ; R 4 is as defined in claim 1.
The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or its mixture form, or its pharmaceutically acceptable salt, which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

Z, Y, R 0 , R 1 , R 4 and n 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, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIaa) or general formula (IIbb) or its tautomer, meso form, and racemate , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

Z, Y, R 0 , R 1 , R 4 and n 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, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R 0 is -C(O)CHR 5 R 6 ;

Z, R 1 , R 4 , R 5 , R 6 and n are as defined in claim 1.
The compound represented by the general formula (I) according to claim 6 or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,

Wherein: R 5 is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by -NR 9 R 10 ; R 9 and R 10 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl group and 3 to 6 membered cycloalkyl group, wherein the C 1-6 alkyl group is optionally substituted by one or more selected from 3 to 6 membered cycloalkyl group and 3 to 6 membered heterocyclic group R 6 is a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group, wherein the 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group is optionally selected from halogen, C 1- 6 Alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy are substituted by one or more substituents.
The compound represented by the general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV) or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R 0 is -C(O)NHCHR 5 R 6 ;

Z, R 1 , R 2 , R 4 , R 5 , R 6 and n are as defined in claim 1.
The compound represented by the general formula (I) according to claim 8 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein: R 5 is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a hydroxyl group; R 6 is a 6 to 10 membered aryl group or a 5 to 10-membered heteroaryl, wherein the 6 to 10-membered aryl or 5- to 10-membered heteroaryl is optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 One or more substituents in the halogenated alkyl group and the C 1-6 halogenated alkoxy group are substituted.
The compound represented by the general formula (I) according to any one of claims 1 to 5 or 8 to 9 or its tautomer, meso, racemate, enantiomer, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 2 is -NR 7 R 8 ; R 7 and R 8 are the same or different, and each independently is a hydrogen atom or C 1-6 alkyl.
The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an O atom.
The compound represented by the general formula (I) according to any one of claims 1 to 5, 10 to 11, or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 0 is -C(O)CHR 5 R 6 or -C(O)NHCHR 5 R 6 ; R 5 is C 1- 6 Alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more substituents selected from hydroxyl and -NR 9 R 10 ; R 9 and R 10 are the same or different, and are independently selected From a hydrogen atom, a C 1-6 alkyl group and a 3 to 6 membered cycloalkyl group, wherein the C 1-6 alkyl group is optionally selected from 3 to 6 membered cycloalkyl groups, 3 to 6 membered heterocyclic groups, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents; R 6 is 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group, wherein the 6 to 10 membered heteroaryl group The membered aryl group or the 5- to 10-membered heteroaryl group is optionally selected from one of halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy Or substituted by multiple substituents.
The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 14 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from any of the following compounds:
A compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salt,

among them:

R w is an amino protecting group;

Y is N atom or CR 2 ;

Q is a CH or N atom; the condition is that when Y is CR 2 , Q is a N atom;

Z is O atom or NR 3 ;

G 1 and G 2 are the same or different, and are each independently selected from CR 4 or N atoms;

R 0 is -C(O)CHR 5 R 6 or -C(O)NHCHR 5 R 6 ;

R 1 is selected from hydrogen atom, halogen, alkyl and haloalkyl;

R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR 7 R 8 , nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from amino, -NR 7 R 8 , halogen, alkoxy, haloalkyl, cyano, nitro, hydroxy, Substituted by one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 3 is 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;

R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;

R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From -NR 9 R 10 , -OR 11 , oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, One or more substituents in heterocyclic group, aryl group and heteroaryl group;

R 6 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;

R 7 and R 8 are the same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 9 and R 10 are the same or different, and are each independently selected from a hydrogen atom, R m , halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from one of cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;

R 11 is selected from hydrogen atom, R n , alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R m is an amino protecting group;

R n is a hydroxyl protecting group;

n is 0, 1, 2, 3, or 4.
The compound represented by the general formula (IA) according to claim 16 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

Wherein Boc is tert-butoxycarbonyl; SEM is (trimethylsilyl)ethoxymethyl; TBS is tert-butyldimethylsilyl.
A method for preparing the compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IA) removes the amino protecting group to obtain the compound of general formula (I),

among them:

R w is an amino protecting group;

G 1 , G 2 , Q, Z, Y, R 0 , R 1 and n are as defined in claim 1.
A pharmaceutical composition containing the compound represented by the general formula (I) according to any one of claims 1 to 15 or its tautomer, mesosome, racemic Isomers, 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 15 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicine for inhibiting AKT1/2/3 (AKTpan).
The compound represented by the general formula (I) according to any one of claims 1 to 15 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for the treatment and/or prevention of tumors.
The compound represented by the general formula (I) according to any one of claims 1 to 15 or its tautomer, meso, racemate, enantiomer, diastereomer The use of a construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 in the preparation of a medicament for the treatment or prevention of cancer; wherein the cancer is preferably selected from ovarian cancer , Breast cancer, prostate cancer, glioma, glioma, stomach cancer, fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, Cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck cancer, multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera Disease, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.